Bicylic compounds and methods of use

ABSTRACT

The present invention provides compounds that modulate protein function, specifically phosphodiesterase 4 (PDE4). The invention provides methods of treating, ameliorating, and/or preventing diseases, disorders, and conditions associated with PDE4. Compositions, including in combination with other inflammatory mediators, are also provided.

BACKGROUND OF THE INVENTION Field of the Invention

Compounds, methods of making such compounds, pharmaceutical compositionsand medicaments comprising such compounds, and methods of using suchcompounds to treat, prevent or diagnose diseases, disorders, orconditions associated with phosphodiesterase 4 (PDE4) malfunction areprovided.

Description of the Related Technology

Aberrant protein function, and/or protein imbalance is a hallmark ofmany disease states. For example, the functioning of the immune systemis finely balanced by the activities of pro-inflammatory andanti-inflammatory mediators or cytokines. Some cytokines promoteinflammation (pro-inflammatory cytokines), whereas other cytokinessuppress the activity of the pro-inflammatory cytokines(anti-inflammatory cytokines). For example, IL-4, IL-10, and IL-13 arepotent activators of B lymphocytes, and also act as anti-inflammatoryagents. They are anti-inflammatory cytokines by virtue of their abilityto suppress genes for pro-inflammatory cytokines such as IL-1, TNF, andchemokines.

Unregulated activities of these mediators can lead to the development ofserious inflammatory conditions. For example, autoimmune diseases arisewhen immune system cells (lymphocytes, macrophages) become sensitizedagainst the “self.” Lymphocytes, as well as macrophages, are usuallyunder control in this system. However, a misdirection of the systemtoward the body's own tissues may happen in response to stillunexplained triggers. One hypothesis is that lymphocytes recognize anantigen which mimics the “self” and a cascade of activation of differentcomponents of the immune system takes place, ultimately leading totissue destruction. Genetic predisposition has also been postulated tobe responsible for autoimmune disorders.

For example, phosphodiesterase 4 (PDE4) is involved in the cytokineproduction of inflammatory cells, angiogenesis, and the functionalproperties of other cell types such as keratinocytes, in part, throughdegradation of cyclic adenosine monophosphate (cAMP). cAMP is animportant second messenger that regulates inflammatory responses.Accordingly, inhibitors of PDE4 may block the synthesis of severalpro-inflammatory cytokines and chemokines, such as tumor necrosis factoralpha, interleukin 23, CXCL9, and CXCL10 in multiple cell types, and mayinterfere with the production of leukotriene B4, inducible nitric oxidesynthase, and matrix metalloproteinases. This interference reducescertain inflammatory processes, such as dendritic cell infiltration,epidermal skin thickening, and joint destruction, for example inpsoriasis and other inflammatory and/or autoimmune diseases such asarthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis,Behcet's disease, inflammatory bowel diseases (e.g., Crohn's disease andulcerative colitis), psoriasis, atopic dermatitis, and contactdermatitis.

Psoriasis is an autoimmune skin disease caused by pro-inflammatorycytokines, interferon gamma (IFN-γ) and TNF-α. The psoriatic immuneresponse involves monocytes, dendritic cells, neutrophils and T cells,which all contribute to aberrant keratinocyte proliferation. PDE4inhibition may reduce production of multiple mediators including TNF-α,IFN-γ, CXCL9 (monokine induced by IFN-γ, or MIG), CXCL10 (IFN-γ-inducedprotein of 10 kDa, or IP-10), IL-2, IL-12, IL-23, macrophageinflammatory protein-1-alpha (MIP-1α), monocyte chemoattractantprotein-1 and granulocyte macrophage-colony stimulating factor (GM-CSF)from PBMCs. Thus, there is a need for small molecule PDE4 inhibitors.

SUMMARY OF THE INVENTION

The compounds disclosed in the present application have been discoveredto exert surprising and unexpected biological effects. In particular,the compounds disclosed in the present application may reduceinflammation, cellular cAMP levels, and inhibit PDE4.

Some embodiments provide a compound of Formula (I), Formula (II), or apharmaceutically acceptable salt of any of the foregoing,

In some embodiments, X and X₁ are each independently CH₂, C═O, SO, SO₂,or CH₂CO.

In some embodiments, Y is H, deuterium, halogen, or an optionallysubstituted C₁-C₆ alkyl.

In some embodiments, R₁ is H, deuterium, hydroxy, halogen, nitro, cyano,optionally substituted C₁-C₆ alkoxy, —NH₂, —NHR_(1A), —NR_(1A)R_(1B),—NHC(O)R_(1C), —NR_(1A)C(O)R_(1C), —NHSO₂R_(1C), —NR_(1A)SO₂R_(1C),—N[C(O)R_(1A)][C(O)R_(1C)], an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or anoptionally substituted 5 to 10 membered heteroaryl.

In some embodiments, R_(1A), R_(1B), and R_(1C) are independentlyselected from an optionally substituted C₁-C₆ alkyl, an optionallysubstituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 memberedheterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionallysubstituted 5 to 10 membered heteroaryl.

In some embodiments, R₂ is hydroxy, —NH₂, —NHR_(1A), —NR_(1A)R_(1B), anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, anoptionally substituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10membered heteroaryl.

In some embodiments, R₃, R₆, and R₇ are independently selected from ahydrogen, a deuterium, a halogen, an optionally substituted C₁-C₆ alkyl,an optionally substituted C₁-C₆ alkoxy, an optionally substituted C₃-C₆cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, anoptionally substituted C₆-C₁₀ aryl, and an optionally substituted 5 to10 membered heteroaryl.

In some embodiments, R₄ and R₅ are independently selected from anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, anoptionally substituted C₆-C₁₀ aryl, and an optionally substituted 5 to10 membered heteroaryl.

In some embodiments, R₄ and R₅, together with the atoms to which theyare attached, form an optionally substituted 5 or 6 memberedheterocyclyl.

In some embodiments, R₈ is hydrogen or deuterium. In some embodiments,R₈ is hydrogen. In other embodiments, R₈ is deuterium.

In some embodiments, when R₂ is an optionally substituted C₁-C₆ alkyl,at least one of R₄ and R₅ is an optionally substituted C₃-C₆ cycloalkyl,an optionally substituted 3 to 10 membered heterocyclyl, an optionallysubstituted C₆-C₁₀ aryl, an optionally substituted 5 to 10 memberedheteroaryl, or R₄ and R₅, together with the atoms to which they areattached, form an optionally substituted 5 or 6 membered heterocyclyl.In some embodiments, when R₂ is an optionally substituted C₁-C₄ alkyl orNH(C₁-C₆ alkyl), at least one of R₄ and R₅ is an optionally substitutedcyclopropyl. In some embodiments, when R₄ and R₅ are each independentlyan optionally substituted C₁-C₆ alkyl, R₂ is an optionally substitutedC₃-C₆ cycloalkyl, an optionally substituted 3 to 10 memberedheterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionallysubstituted 5 to 10 membered heteroaryl. In some embodiments, R₂, R₄,and R₅ are not all an optionally substituted C₁-C₆ alkyl.

In some embodiments, R₂ is hydroxy, —NH₂, —NHR_(1A), or —NR_(1A)R_(1B),and R₄ and R₅ are each independently an optionally substituted C₁-C₆alkyl, or R₄ and R₅, together with the atoms to which they are attached,form an optionally substituted 5 or 6 membered heterocyclyl.

In some embodiments, when a C₁-C₆ alkyl, a C₁-C₆ alkoxy, a C₃-C₆cycloalkyl, a C₆-C₁₀ aryl, a 3 to 10 membered heterocyclyl, or a 5 to 10membered heteroaryl is substituted, the substituted substituents areindependently selected from a deuterium, an oxo, a halogen, cyano, anitro, an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₁-C₆ haloalkyl, an optionally substituted C₁-C₆ alkoxy, an optionallysubstituted C₃-C₆ cycloalkyl, an optionally substituted C₆-C₁₀ aryl, anoptionally substituted 3 to 10 membered heterocyclyl, an optionallysubstituted 5 to 10 membered heteroaryl, —C(O)R_(A), —C(O)OR_(A),—C(O)NR_(B)R_(C), —OR_(A), —OC(O)R_(A), —OC(O)NR_(B)R_(C), —OS(O)R_(A),—OS(O)₂R_(A), —OS(O)NR_(B)R_(C), —OS(O)₂NR_(B)R_(C), —NR_(B)R_(C),—NR_(A)C(O)R_(A), —NR_(A)C(O)OR_(A), —NR_(A)C(O)NR_(B)R_(C),—NR_(A)S(O)R_(A), —NR_(A)S(O)₂R_(A), —NR_(A)S(O)NR_(B)R_(C),—NR_(A)S(O)₂NR_(B)R_(C), —SR_(A), —S(O)R_(A), —S(O)₂R_(A),—S(O)NR_(B)R_(C), and —S(O)₂NR_(B)R_(C).

In some embodiments, each R_(A), R_(B), and R_(C) are independentlyselected from a hydrogen, an unsubstituted C₁-C₆ alkyl, an unsubstitutedC₂-C₆ alkenyl, an unsubstituted C₃-C₆ cycloalkyl, an unsubstituted 3 to10 membered heterocyclyl, an unsubstituted C₆-C₁₀ aryl, and anunsubstituted 5 to 10 membered heteroaryl.

In some embodiments, R_(B) and R_(C), together with the nitrogen atom towhich they are attached, form an optionally substituted 3 to 10 memberedheterocyclyl.

In some embodiments, Y is H. In some embodiments, Y is deuterium. Insome embodiments, Y is halogen. In some embodiments, Y is an optionallysubstituted C₁-C₆ alkyl.

In some embodiments, one of X and X₁ is CH₂ and the other is C═O. Insome embodiments, X and X₁ are each CH₂. In some embodiments, X and X₁are each C═O. In some embodiments, one of X and X₁ is CH₂ and the otheris SO. In some embodiments, one of X and X₁ is CH₂ and the other is SO₂.In some embodiments, one of X and X₁ is CH₂ and the other is CH₂CO. Insome embodiments, one of X and X₁ is C═O and the other one of X and X₁is SO. In some embodiments, one of X and X₁ is C═O and the other one ofX and X₁ is SO₂. In some embodiments, one of X and X₁ is C═O and theother is CH₂CO.

In some embodiments, R₁ is —NHR_(1A), —NR_(1A)R_(1B), —NHC(O)R_(1C) or—NR_(1A)C(O)R_(1C). In some embodiments, R₁ is—N[C(O)R_(1A)][C(O)R_(1C)]. In some embodiments, R₁ is —NHC(O)R_(1C). Insome embodiments, R_(1A), R_(1B), and R_(1C) are independently anoptionally substituted C₁-C₆ alkyl or an optionally substituted C₃-C₆cycloalkyl. In some embodiments, R_(1C) is an optionally substitutedC₁-C₆ alkyl. In some embodiments, R_(1C) is an unsubstituted C₁-C₆alkyl.

In some embodiments, R₃, R₆, and R₇ are independently selected from ahydrogen, a halogen, and an optionally substituted C₁-C₆ alkyl. In someembodiments, R₃, R₆, and R₇ are each hydrogen.

In some embodiments, R₂ is an optionally substituted C₁-C₆ alkyl and oneof R₄ and R₅ is an optionally substituted C₁-C₆ alkyl and the other isan optionally substituted C₃-C₆ cycloalkyl or an optionally substituted3 to 10 membered heterocyclyl.

In some embodiments, R₂ is an unsubstituted C₁-C₆ alkyl and one of R₄and R₅ is an unsubstituted C₁-C₆ alkyl and the other is an optionallysubstituted C₃-C₆ cycloalkyl or an optionally substituted 3 to 10membered heterocyclyl.

In some embodiments, R₂ is an optionally substituted C₃-C₆ cycloalkyl,an optionally substituted 3 to 10 membered heterocyclyl, an optionallysubstituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 memberedheteroaryl, and R₄ and R₅ are independently an optionally substitutedC₁-C₆ alkyl.

In some embodiments, R₂ is an optionally substituted C₃-C₆ cycloalkyl,an optionally substituted 3 to 10 membered heterocyclyl, an optionallysubstituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 memberedheteroaryl, and R₄ and R₅ are independently unsubstituted C₁-C₆ alkyl.

In some embodiments, R₂ is hydroxy, —NH₂, —NHR_(1A), or —NR_(1A)R_(1B),and R_(1A) and R_(1B) are each independently an optionally substitutedC₁-C₆ alkyl or an optionally substituted C₆-C₁₀ aryl.

In some embodiments, R₄ and R₅, together with the atoms to which theyare attached, form an optionally substituted 5 or 6 memberedheterocyclyl.

In some embodiments, R₄ and R₅, together with the atoms to which theyare attached, form an unsubstituted 5 or 6 membered heterocyclyl.

In some embodiments, R₄ and R₅, together with the atoms to which theyare attached, form an unsubstituted 5 membered heterocyclyl.

In some embodiments, R₄ and R₅, together with the atoms to which theyare attached, form an unsubstituted 6 membered heterocyclyl.

In some embodiments, the compound Formula (I) or the compound of Formula(II) is selected from:

or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the compound is a pharmaceutically acceptable salt.

Some embodiments provide a pharmaceutical composition comprising acompound of any of Formula (I), Formula (II), or a pharmaceuticallyacceptable salt of any of the foregoing, and at least onepharmaceutically acceptable carrier.

In some embodiments, the composition is formulated for oral, parenteral,topical, ophthalmic, inhalation, nasal, or intravenous administration.In some embodiments, the composition is formulated as a tablet orcapsule.

In some embodiments, the pharmaceutical composition further comprises asecond therapeutic agent. In some embodiments, the second therapeuticagent is selected from the group consisting of anti-inflammatory agents,anti-cancer agents, immunostimulatory agents, and immunosuppressiveagents. In some embodiments, the second therapeutic agent isanti-inflammatory agent or an immunosuppressive agent.

Some embodiments provide a method of treating, ameliorating, orpreventing a disease, disorder, or condition associated with TNF-α,INF-γ, IL-2, IL-17, IL-23, or a combination thereof, comprisingadministering a therapeutically effective amount of a compound of anyone of Formula (I), Formula (II), or a pharmaceutically acceptable saltof any of the foregoing, or a composition comprising any one of Formula(I) or Formula (II) to a subject in need thereof.

In some embodiments, the disease, disorder, or condition is selectedfrom the group consisting of arthritis, ankylosing spondylitis,osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatorybowel diseases (e.g., Crohn's disease and ulcerative colitis),psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis,and combinations thereof.

Some embodiments provide a method of treating, ameliorating, orpreventing a disease, disorder, or condition associated with PDE4,comprising administering a therapeutically effective amount of acompound of any one of Formula (I), Formula (II), or a pharmaceuticallyacceptable salt of any of the foregoing, or a composition comprising anyone of Formula (I) or Formula (II) to a subject in need thereof.

In some embodiments, the disease, disorder, or condition is selectedfrom the group consisting of arthritis, ankylosing spondylitis,osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatorybowel diseases (e.g., Crohn's disease and ulcerative colitis),psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis,and combinations thereof.

In some embodiments, the compound or composition is administered incombination with a second therapeutic agent.

In some embodiments, the second therapeutic agent is selected from thegroup consisting of anti-inflammatory agents, anti-cancer agents,immunostimulatory agents, and immunosuppressive agents. In someembodiments, the second therapeutic agent is an anti-inflammatory agentor an immunosuppressive agent.

Some embodiments provide a method of decreasing expression of a proteinselected from TNF-α, INF-γ, IL-2, IL-17, IL-23, or a combinationthereof, comprising contacting a cell with a compound of any one ofFormula (I) or Formula (II), or a pharmaceutically acceptable salt ofany of the foregoing. In some embodiments, the protein is TNF-α.

Some embodiments provide a method of inhibiting PDE4 activity,comprising contacting a cell with a compound of any one of Formula (I)or Formula (II), or a pharmaceutically acceptable salt of any of theforegoing.

Some embodiments provide a method of treating psoriasis, comprisingtopically administering a therapeutically effective amount of acomposition comprising any one of Formula (I) or Formula (II), or apharmaceutically acceptable salt of any of the foregoing, to a subjectin need thereof.

In some embodiments, the subject is known to possess wild-type PDE4. Insome embodiments, the subject is known to possess wild-type TNF-α. Insome embodiments, the subject is known to possess wild-type INF-γ, IL-2,IL-17, or IL-23. In some embodiments, the subject is known to possessaberrant PDE4. In some embodiments, the subject is known to possessaberrant TNF-α. In some embodiments, the subject is known to possessaberrant INF-γ, IL-2, IL-17, or IL-23.

In some embodiments, the cell is known to possess wild-type PDE4. Insome embodiments, the cell is known to possess wild-type TNF-α. In someembodiments, the cell is known to possess wild-type INF-γ, IL-2, IL-17,or IL-23. In some embodiments, the cell is known to possess aberrantPDE4. In some embodiments, the cell is known to possess aberrant TNF-α.In some embodiments, the cell is known to possess aberrant INF-γ, IL-2,IL-17, or IL-23.

Any of the features of an embodiment is applicable to all embodimentsidentified herein. Moreover, any of the features of an embodiment isindependently combinable, partly or wholly with other embodimentsdescribed herein in any way, e.g., one, two, or three or moreembodiments may be combinable in whole or in part. Further, any of thefeatures of an embodiment may be made optional to other embodiments. Anyembodiment of a method can comprise another embodiment of a compound,and any embodiment of a compound can be configured to perform a methodof another embodiment.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise. As used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

The term “protein malfunction,” as used herein, refers to a protein orproteins not properly performing its intended biological function. Forexample, overexpression or underexpression and mutations instructure/function constitute a protein malfunction. Likewise, a proteinor proteins that are expressed normally, and function normally, but areunable to perform their intended biological function (i.e., suppresstumor growth) are also malfunctioning proteins.

The terms “co-administration” and similar terms as used herein are broadterms, and are to be given their ordinary and customary meaning to aperson of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation toadministration of the selected therapeutic agents to a single patient,and are intended to include treatment regimens in which the agents areadministered by the same or different route of administration or at thesame or different time.

The terms “effective amount” and “therapeutically effective amount” arebroad terms, and are to be given their ordinary and customary meaning toa person of ordinary skill in the art (and are not to be limited to aspecial or customized meaning), and refer without limitation to asufficient amount of an agent or a compound being administered whichwill relieve to some extent one or more of the symptoms of the diseaseor condition being treated. The result can be reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in disease symptoms. An appropriate “effective”amount in any individual case may be determined using techniques, suchas a dose escalation study. Where a drug has been approved by the U.S.Food and Drug Administration (FDA) or a counterpart foreign medicinesagency, a “therapeutically effective amount” an optionally refers to thedosage approved by the FDA or its counterpart foreign agency fortreatment of the identified disease or condition.

The term “pharmaceutical combination” as used herein is a broad term,and is to be given its ordinary and customary meaning to a person ofordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a product thatresults from the mixing or combining of more than one active ingredientand includes both fixed and non-fixed combinations of the activeingredients. The term “fixed combination” means that the activeingredients, e.g., a compound of a preferred embodiment and a co-agent,are both administered to a patient simultaneously in the form of asingle entity or dosage. The term “non-fixed combination” means that theactive ingredients, e.g., a compound of a preferred embodiment and aco-agent, are administered to a patient as separate entities eithersimultaneously, concurrently or sequentially with no specificintervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g., the administration of three or moreactive ingredients.

As used herein, any “R” group(s) such as, without limitation, R₂, R₃,R₄, R₅, R₆, R₉, and Rio represent substituents that can be attached tothe indicated atom. An R group may be substituted or an unsubstituted.If two “R” groups are described as being “taken together” the R groupsand the atoms they are attached to can form a cycloalkyl, aryl,heteroaryl, or heterocycle. For example, without limitation, if R² andR³, or R², R³, or R⁴, and the atom to which it is attached, areindicated to be “taken together” or “joined together” it means that theyare covalently bonded to one another to form a ring:

Whenever a group is described as being “an optionally substituted” thatgroup may be an unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being “anunsubstituted or substituted” if substituted, the substituent may beselected from one or more the indicated substituents. If no substituentsare indicated, it is meant that the indicated “an optionallysubstituted” or “substituted” group may be individually andindependently substituted with one or more group(s) individually andindependently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl,heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl,alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protectedC-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy,trihalomethanesulfonyl, trihalomethanesulfonamido, amino,mono-substituted amino group and di-substituted amino group, andprotected derivatives thereof.

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers referto the number of carbon atoms in an alkyl, alkenyl or alkynyl group, orthe number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group. That is, thealkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of thecycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of theheteroaryl or ring of the heteroalicyclyl can contain from “a” to “b”,inclusive, carbon atoms. Thus, for example, a “C₁ to C₄ alkyl” grouprefers to all alkyl groups having from 1 to 4 carbons, that is, CH₃—,CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and(CH₃)₃C—. If no “a” and “b” are designated with regard to an alkyl,alkenyl, alkynyl, cycloalkyl cycloalkenyl, cycloalkynyl, aryl,heteroaryl or heteroalicyclyl group, the broadest range described inthese definitions is to be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl” or similar designations. By way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.Typical alkyl groups include, but are in no way limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, andhexyls. The alkyl group may be substituted or an unsubstituted.Substituted alkyl groups include, but are not limited to benzyl,substituted benzyl, aminoalkyl, substituted aminoalkyl, carboxyalkyl,alkoxyalkyl, and the like.

As used herein, “alkenyl” refers to an alkyl group, as defined herein,that contains in the straight or branched hydrocarbon chain one or moredouble bonds. An alkenyl group may be an unsubstituted or substituted.Typical alkyl groups include, but are in no way limited to, vinyl,allyl, 1-propenyl, and 2-propenyl.

As used herein, “alkynyl” refers to an alkyl group as defined herein,that contains in the straight or branched hydrocarbon chain one or moretriple bonds. An alkynyl group may be an unsubstituted or substituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused, bridged, or spiro fashion. Cycloalkyl groups can contain 3 to 10atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl groupmay be an unsubstituted or substituted. Typical cycloalkyl groupsinclude, but are in no way limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein). Whencomposed of two or more rings, the rings may be connected together in afused, bridged, or spiro fashion. A cycloalkenyl group may be anunsubstituted or substituted.

As used herein, “cycloalkynyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more triple bonds in atleast one ring. If there is more than one triple bond, the triple bondscannot form a fully delocalized pi-electron system throughout all therings. When composed of two or more rings, the rings may be joinedtogether in a fused, bridged, or spiro fashion. A cycloalkynyl group maybe an unsubstituted or substituted.

As used herein, “carbocyclyl” or “cyclic hydrocarbyl” refers to allcarbon ring systems. Such systems can be unsaturated, can include someunsaturation, or can contain some aromatic portion, or be all aromatic.Carbocyclyl group can contain from 3 to 30 carbon atoms. A carbocyclylgroup may be an unsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including, e.g., fused, bridged, orspiro ring systems where two carbocyclic rings share a chemical bond,e.g., one or more aryl rings with one or more aryl or non-aryl rings)that has a fully delocalized pi-electron system throughout at least oneof the rings. The number of carbon atoms in an aryl group can vary. Forexample, the aryl group can be a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group,or a C₆ aryl group. Examples of aryl groups include, but are not limitedto, benzene, naphthalene, and azulene. An aryl group may be substitutedor an unsubstituted.

As used herein, “heterocyclyl” refers to mono- or polycyclic ringsystems including at least one heteroatom (e.g., O, N, S), and up tofive heteroatoms, for example, 1, 2, 3, 4, or 5 heteroatoms. Suchsystems can be unsaturated, can include some unsaturation, or cancontain some aromatic portion, or be all aromatic. A heterocyclyl groupcan contain from 3 to 30 atoms. A heterocyclyl group may be anunsubstituted or substituted. Examples of heterocycles include, but arenot limited to oxirane, aziridine, thiirane, diazidiridine, oxaziridine,azetidine, oxetane, thietane, oxazetidine, pyrrolidine, tetrahydrofuran,tetrahydrothiophene, imidazoline, pyrazolidine, oxazolidine,isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane,piperidine, tetrahydropyran, thiane, piperazine, morpholine,thiomorpholine, dioxane, dithiane, azepine, diazepine, oxepane,dioxapane, oxazepane, thiazepane, thiepane, azocane, diazocane, oxocane,dioxocane, thiocane, dithiocane, oxazacane, and thiazacane. Aheterocyclyl group may be substituted or unsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system having a least one ring with a fullydelocalized pi-electron system) that contain(s) at least heteroatom,that is, an element other than carbon, including but not limited to,nitrogen, oxygen, and sulfur, and at least one aromatic ring and up tofive heteroatoms, for example, 1, 2, 3, 4, or 5 heteroatoms. The numberof atoms in the ring(s) of a heteroaryl group can vary. For example, theheteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atomsin the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term“heteroaryl” includes fused ring systems where two rings, such as atleast one aryl ring and at least one heteroaryl ring, or at least twoheteroaryl rings, share at least one chemical bond. Examples ofheteroaryl rings include, but are not limited to, furan, furazan,thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline,isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Aheteroaryl group may be substituted or an unsubstituted.

As used herein, “heteroalicyclic” or “heteroalicyclyl” refers to three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic, and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may an optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatoms areindependently selected from oxygen, sulfur, and nitrogen. A heterocyclemay further contain one or more carbonyl or thiocarbonylfunctionalities, so as to make the definition include oxo-systems andthio-systems such as lactams, lactones, cyclic imides, cyclicthioimides, and cyclic carbamates. When composed of two or more rings,the rings may be joined together in a fused, bridged, or spiro fashion.Additionally, any nitrogens in a heteroalicyclic may be quaternized.Heteroalicyclyl or heteroalicyclic groups may be an unsubstituted orsubstituted. Examples of such “heteroalicyclic” or “heteroalicyclyl”groups include but are not limited to, 1,3-dioxin, 1,3-dioxane,1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane,1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane,1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide,succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine,hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine,imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine,oxirane, piperidine N-oxide, piperidine, piperazine, pyrrolidine,pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine,2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran,thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, andtheir benzo-fused analogs (e.g., benzimidazolidinone,tetrahydroquinoline, 3,4-methylenedioxyphenyl).

“Lower alkylene groups” are straight-chained —CH₂— tethering groups,forming bonds to connect molecular fragments via their terminal carbonatoms. Lower alkylene groups contain from 1 to 6 carbon atoms. Examplesinclude but are not limited to methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), and butylene (—CH₂CH₂CH₂CH₂—). A lower alkylenegroup can be substituted by replacing one or more hydrogen of the loweralkylene group with a substituent(s) listed under the definition of“substituted.”

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group, asdefined above, connected, as a substituent, via a lower alkylene group,as described above. The lower alkylene and aryl group of an aralkyl maybe substituted or an unsubstituted. Examples include but are not limitedto benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to aheteroaryl group, as defined above, connected, as a substituent, via alower alkylene group, as defined above. The lower alkylene andheteroaryl group of heteroaralkyl may be substituted or anunsubstituted. Examples include but are not limited to 2-thienylalkyl,3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl,isoxazolylalkyl, and imidazolylalkyl, and their benzo-fused analogs.

A “(heteroalicyclyl)alkyl” is a heterocyclic or a heteroalicyclylicgroup, as defined above, connected, as a substituent, via a loweralkylene group, as defined above. The lower alkylene and heterocyclic ora heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or anunsubstituted. Examples include but are not limited totetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl,(piperidin-4-yl)propyl, (tetrahydro-2H-thiopyran-4-yl)methyl, and(1,3-thiazinan-4-yl)methyl.

As used herein, “alkoxy” refers to the formula —OR wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl or acycloalkynyl, as defined above. A non-limiting list of alkoxys ismethoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, and tert-butoxy. An alkoxy may be substituted oran unsubstituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, oraryl, as defined above, connected, as substituents, via a carbonylgroup. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl.An acyl may be substituted or an unsubstituted.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkylmay be substituted or an unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups includebut are not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. Ahaloalkyl may be substituted or an unsubstituted.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups includebut are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or an unsubstituted.

As used herein, “aryloxy” and “arylthio” refers to RO— and RS—, in whichR is an aryl, as defined above, such as but not limited to phenyl. Bothan aryloxy and arylthio may be substituted or an unsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, asdefined above. A sulfenyl may be substituted or an unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to sulfenyl. A sulfinyl may be substitutedor an unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to sulfenyl. A sulfonyl may be substituted or anunsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or(heteroalicyclyl)alkyl, as defined herein. An O-carboxy may besubstituted or an unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or an unsubstituted.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or an unsubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group wherein Xis a halogen.

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R_(A))—”group wherein X is a halogen and R_(A) hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl.

The term “amino” as used herein refers to a —NH₂ group.

As used herein, the term “hydroxy” refers to a —OH group.

A “cyano” group refers to a “—CN” group.

The term “azido” as used herein refers to a —N₃ group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—CNS” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “mercapto” group refers to an “—SH” group.

A “carbonyl” group refers to a C═O group.

An “S-sulfonamido” group refers to a “—SO₂N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.An S-sulfonamido may be substituted or an unsubstituted.

An “N-sulfonamido” group refers to a “RSO₂N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.An N-sulfonamido may be substituted or an unsubstituted.

An “O-carbamyl” group refers to a “—OC(═O)N(R_(A)R_(B))” group in whichR_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.An O-carbamyl may be substituted or an unsubstituted.

An “N-carbamyl” group refers to an “ROC(═O)N(R_(A))—” group in which Rand R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.An N-carbamyl may be substituted or an unsubstituted.

An “O-thiocarbamyl” group refers to a “—OC(═S)—N(R_(A)R_(B))” group inwhich R_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.An O-thiocarbamyl may be substituted or an unsubstituted.

An “N-thiocarbamyl” group refers to an “ROC(═S)N(R_(A))—” group in whichR and R_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.An N-thiocarbamyl may be substituted or an unsubstituted.

A “C-amido” group refers to a “—C(═O)N(R_(A)R_(B))” group in which R_(A)and R_(B) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. AC-amido may be substituted or an unsubstituted.

An “N-amido” group refers to a “RC(═O)N(R_(A))—” group in which R andR_(A) can be independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above.An N-amido may be substituted or an unsubstituted.

A “urea” group refers to a “—N(R_(A)R_(B))—C(═O)—N(R_(A)R_(B))—” groupin which R_(A) and R_(B) can be independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl,heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined above. Aurea group may be substituted or an unsubstituted.

A “thiourea” group refers to a “—N(R_(A)R_(B))—C(═S)—N(R_(A)R_(B))—”group in which R_(A) and R_(B) can be independently hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, asdefined above. A thiourea group may be substituted or an unsubstituted.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine, and iodine.

In all of the definitions described herein, the terms used to define anew term are as previously defined herein.

Where the numbers of substituents is not specified (e.g., haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two, or three atoms.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

The terms “protecting group” and “protecting groups” as used hereinrefer to any atom or group of atoms that is added to a molecule in orderto prevent existing groups in the molecule from undergoing unwantedchemical reactions. Examples of protecting group moieties are describedin T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W. McOmie,Protective Groups in Organic Chemistry Plenum Press, 1973, both of whichare hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls (e.g., t-butoxycarbonyl(BOC), acetyl, or isobutyryl); arylalkylcarbonyls (e.g.,benzyloxycarbonyl or benzoyl); substituted methyl ether (e.g.,methoxymethyl ether); substituted ethyl ether; a substituted benzylether; tetrahydropyranyl ether; silyl ethers (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, ort-butyldiphenylsilyl); esters (e.g., benzoate ester); carbonates (e.g.,methoxymethylcarbonate); sulfonates (e.g., tosylate or mesylate);acyclic ketal (e.g., dimethyl acetal); cyclic ketals (e.g., 1,3-dioxaneor 1,3-dioxolanes); acyclic acetal; cyclic acetal; acyclic hemiacetal;cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or1,3-dithiolane); and triarylmethyl groups (e.g., trityl;monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr); or4,4′,4″-trimethoxytrityl (TMTr)).

“Leaving group” as used herein refers to any atom or moiety that iscapable of being displaced by another atom or moiety in a chemicalreaction. More specifically, in some embodiments, “leaving group” refersto the atom or moiety that is displaced in a nucleophilic substitutionreaction. In some embodiments, “leaving groups” are any atoms ormoieties that are conjugate bases of strong acids. Examples of suitableleaving groups include, but are not limited to, tosylates and halogens.Non-limiting characteristics and examples of leaving groups can befound, for example in Organic Chemistry, 2d ed., Francis Carey (1992),pages 328-331; Introduction to Organic Chemistry, 2d ed., AndrewStreitwieser and Clayton Heathcock (1981), pages 169-171; and OrganicChemistry, 5^(th) ed., John McMurry (2000), pages 398 and 408; all ofwhich are incorporated herein by reference for the limited purpose ofdisclosing characteristics and examples of leaving groups.

The term “pharmaceutically acceptable salt” as used herein is a broadterm, and is to be given its ordinary and customary meaning to a personof ordinary skill in the art (and is not to be limited to a special orcustomized meaning), and refers without limitation to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example formic acid, acetic acid, propionic acid,glycolic acid, pyruvic acid, malonic acid, maleic acid, fumaric acid,trifluoroacetic acid, benzoic acid, cinnamic acid, mandelic acid,succinic acid, lactic acid, malic acid, tartaric acid, citric acid,ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonicacid, p-toluensulfonic acid, salicylic acid, stearic acid, muconic acid,butyric acid, phenylacetic acid, phenylbutyric acid, valproic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, 2-naphthalenesulfonic acid, or naphthalenesulfonic acid.Pharmaceutical salts can also be obtained by reacting a compound with abase to form a salt such as an ammonium salt, an alkali metal salt, suchas a lithium, sodium or a potassium salt, an alkaline earth metal salt,such as a calcium, magnesium or aluminum salt, a salt of organic basessuch as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine, cyclohexylamine,dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine,diethanolamine, triethanolamine, tromethamine, and salts with aminoacids such as arginine and lysine; or a salt of an inorganic base, suchas aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, or the like.

The term “solvate” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to mean that the solvent is complexed with acompound in a reproducible molar ratio, including, but not limited to,0.5:1, 1:1, or 2:1. Thus, the term “pharmaceutically acceptablesolvate,” refers to a solvate wherein the solvent is one that does notcause significant irritation to an organism to which it is administeredand does not abrogate the biological activity and properties of thecompound.

The term “prodrug” as used herein is a broad term, and is to be givenits ordinary and customary meaning to a person of ordinary skill in theart (and is not to be limited to a special or customized meaning), andrefers without limitation to a compound or a pharmaceutical compositionthat can be administered to a patient in a less active or inactive form,which can then be metabolized in vivo into a more active metabolite. Incertain embodiments, upon in vivo administration, a prodrug ischemically converted to the biologically, pharmaceutically, ortherapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processesto the biologically, pharmaceutically, or therapeutically active form ofthe compound.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, or maybe stereoisomeric mixtures, and include all diastereomeric, andenantiomeric forms. In addition it is understood that, in any compounddescribed herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof. Stereoisomers are obtained,if desired, by methods such as, stereoselective synthesis and/or theseparation of stereoisomers by chiral chromatographic columns. In someembodiments, the compounds described herein (for example, compounds ofFormula (I) or Formula (II), and pharmaceutically acceptable salts ofany of the foregoing) are present in a racemic mixture. In someembodiments, the compounds described herein (for example, compounds ofFormula (I) or Formula (II), and pharmaceutically acceptable salts ofany of the foregoing) are in the S-configuration. In some embodiments,the compounds described herein (for example, compounds of Formula (I) orFormula (II), and pharmaceutically acceptable salts of any of theforegoing) are in the R-configuration.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included.

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of the molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. Thus, for example, a substituent depicted as -AE-or

includes the substituent being oriented such that the A is attached atthe leftmost attachment point of the molecule as well as the case inwhich A is attached at the rightmost attachment point of the molecule.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensand/or deuteriums.

It is understood that the compounds described herein can be labeledisotopically or by another other means, including, but not limited to,the use of chromophores or fluorescent moieties, bioluminescent labels,or chemiluminescent labels. Substitution with isotopes such as deuteriummay afford certain therapeutic advantages resulting from greatermetabolic stability, such as, for example, increased in vivo half-lifeor reduced dosage requirements. Each chemical element as represented ina compound structure may include any isotope of said element. Forexample, in a compound structure a hydrogen atom may be explicitlydisclosed or understood to be present in the compound. At any positionof the compound that a hydrogen atom may be present, the hydrogen atomcan be any isotope of hydrogen, including but not limited to hydrogen-1(protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus,reference herein to a compound encompasses all potential isotopic formsunless the context clearly dictates otherwise.

It is understood that the methods and formulations described hereininclude the use of crystalline forms, amorphous phases, and/orpharmaceutically acceptable salts, solvates, hydrates, and conformers ofcompounds of preferred embodiments, as well as metabolites and activemetabolites of these compounds having the same type of activity. Aconformer is a structure that is a conformational isomer. Conformationalisomerism is the phenomenon of molecules with the same structuralformula but different conformations (conformers) of atoms about arotating bond. In specific embodiments, the compounds described hereinexist in solvated forms with pharmaceutically acceptable solvents suchas water, ethanol, or the like. In other embodiments, the compoundsdescribed herein exist in unsolvated form. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, or the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. In addition, the compounds provided herein can existin unsolvated as well as solvated forms. In general, the solvated formsare considered equivalent to the unsolvated forms for the purposes ofthe compounds and methods provided herein. Other forms in which thecompounds of preferred embodiments can be provided include amorphousforms, milled forms and nano-particulate forms.

Likewise, it is understood that the compounds described herein, such ascompounds of preferred embodiments, include the compound in any of theforms described herein (e.g., pharmaceutically acceptable salts,prodrugs, crystalline forms, amorphous form, solvated forms,enantiomeric forms, tautomeric forms, and the like).

Some embodiments provide a compound of Formula (I), Formula (II), or apharmaceutically acceptable salt of any of the foregoing,

In some embodiments, X and X₁ are each independently CH₂, C═O, SO, SO₂,or CH₂CO. In some embodiments, X and X₁ are each independently CH₂ orC═O. In some embodiments, X and X₁ are each CH₂. In other embodiments, Xand X₁ are each C═O. In still other embodiments, one of X and X₁ is C═O,and the other of X and X₁ is CH₂.

In some embodiments, Y is H. In some embodiments, Y is deuterium. Insome embodiments, Y is halogen, for example, fluoro, chloro, or bromo.In some embodiments, Y is an optionally substituted C₁-C₆ alkyl, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, or t-butyl.

In some embodiments, R₁ is —NH₂, —NHR_(1A), —NR_(1A)R_(1B),—NHC(O)R_(1C), —NR_(1A)C(O)R_(1C), —NHSO₂R_(1C), or —NHR_(1A)SO₂R_(1C).In some embodiments, R₁ is —N[C(O)R_(1A)] [C(O)R_(1C)].

In some embodiments, R_(1A), R_(1B), and R_(1C) are independentlyselected from an optionally substituted C₁-C₆ alkyl, an optionallysubstituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 memberedheterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionallysubstituted 5 to 10 membered heteroaryl.

In some embodiments, X and X₁ are each C═O, R₁ is —NHR_(1A), and R_(1A)is an optionally substituted C₁-C₆ alkyl or an optionally substitutedC₃-C₆ cycloalkyl.

In some embodiments, X and X₁ are each C═O, R₁ is —NR_(1A)R_(1B), andR_(1A) and R_(1B) are independently an optionally substituted C₁-C₆alkyl or an optionally substituted C₃-C₆ cycloalkyl, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In some embodiments, X and X₁ are each C═O, R₁ is —NHC(O)R_(1C), andR_(1C) is an optionally substituted C₆-C₁₀ aryl or an optionallysubstituted 5 to 10 membered heteroaryl.

In some embodiments, X and X₁ are each C═O, R₁ is —NR_(1A)C(O)R_(1C),and R_(1A) and R_(1C) are independently an optionally substituted C₁-C₆alkyl, an optionally substituted C₆-C₁₀ aryl, or an optionallysubstituted 5 to 10 membered heteroaryl, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, phenyl,naphthyl, furan, pyrrole, imidazole, thiophene, pyridine, or pyrimidine.

In some embodiments, X and X₁ are each C═O, R₁ is—N[C(O)R_(1A)][C(O)R_(1C)], and R_(1A) and R_(1C) are independently anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₆-C₁₀aryl, or an optionally substituted 5 to 10 membered heteroaryl, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, phenyl, naphthyl, furan, pyrrole, imidazole,thiophene, pyridine, or pyrimidine.

In some embodiments, R₁ is hydroxy. In some embodiments, R₁ is halogen,for example, fluoro, chloro, or bromo. In some embodiments, R₁ is nitro.In some embodiments, R₁ is cyano. In some embodiments, R₁ is optionallysubstituted C₁-C₆ alkoxy. In some embodiments, R₁ is —NH₂. In someembodiments, R₁ is —NHR_(1A), —NR_(1A)R_(1B), —NHC(O)R_(1C),—NR_(1A)C(O)R_(1C), —NHSO₂R_(1C), or —NR_(1A)SO₂R_(1C). In someembodiments, R₁ is —N[C(O)R_(1A)][C(O)R_(1C)]. In some embodiments, R₁is an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₃-C₆ cycloalkyl, an optionally substituted 3 to 10 memberedheterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionallysubstituted 5 to 10 membered heteroaryl. In some embodiments, R₁ is anoptionally substituted C₁-C₆ alkyl. In some embodiments, R₁ is anoptionally substituted C₃-C₆ cycloalkyl. In some embodiments, R₁ is anoptionally substituted 3 to 10 membered heterocyclyl. In someembodiments, R₁ is an optionally substituted C₆-C₁₀ aryl. In someembodiments, R₁ is an optionally substituted 5 to 10 memberedheteroaryl.

In some embodiments, R₂ is an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or anoptionally substituted 5 to 10 membered heteroaryl.

In some embodiments, R₂ is an unsubstituted C₁-C₆ alkyl, anunsubstituted C₃-C₆ cycloalkyl, an unsubstituted 3 to 10 memberedheterocyclyl, an unsubstituted C₆-C₁₀ aryl, or an unsubstituted 5 to 10membered heteroaryl.

In some embodiments, R₂ is an optionally substituted C₁-C₆ alkyl, forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, or t-butyl. In some embodiments, R₂ is an optionallysubstituted C₃-C₆ cycloalkyl, for example, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

In some embodiments, R₃, R₆, and R₇ are independently selected from ahydrogen, a deuterium, a halogen, an optionally substituted C₁-C₆ alkyl,an optionally substituted C₁-C₆ alkoxy, an optionally substituted C₃-C₆cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, anoptionally substituted C₆-C₁₀ aryl, and an optionally substituted 5 to10 membered heteroaryl.

In some embodiments, R₃, R₆, and R₇ are each hydrogen. In someembodiments, one of R₃, R₆, and R₇ is halogen, and the other two arehydrogen. In some embodiments, one of R₃, R₆, and R₇ is an optionallysubstituted C₁-C₆ alkyl, and the other two are hydrogen. In someembodiments, two of R₃, R₆, and R₇ are halogen, and the other one ishydrogen. In some embodiments, two of R₃, R₆, and R₇ are an optionallysubstituted C₁-C₆ alkyl, and the other one is hydrogen.

In some embodiments, R₄ and R₅ are independently selected from anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, anoptionally substituted C₆-C₁₀ aryl, and an optionally substituted 5 to10 membered heteroaryl. In some embodiments, R₄ and R₅ are independentlyselected from an optionally substituted C₁-C₆ alkyl, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, ort-butyl. In some embodiments, R₄ and R₅ are independently an optionallysubstituted C₃-C₆ cycloalkyl, for example, cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In some embodiments, one of R₄ and R₅ is anoptionally substituted C₁-C₆ alkyl and the other is an optionallysubstituted C₃-C₆ cycloalkyl.

In some embodiments, R₄ and R₅, together with the atoms to which theyare attached, form an optionally substituted 5 or 6 memberedheterocyclyl, for example, an optionally substituted dioxolane or anoptionally substituted 1,4-dioxane. In some embodiments, R₄ and R₅,together with the atoms to which they are attached, form anunsubstituted dioxolane or an unsubstituted 1,4-dioxane.

In some embodiments, when R₂ is an optionally substituted C₁-C₆ alkyl,at least one of R₄ and R₅ is an optionally substituted C₃-C₆ cycloalkyl,an optionally substituted 3 to 10 membered heterocyclyl, an optionallysubstituted C₆-C₁₀ aryl, an optionally substituted 5 to 10 memberedheteroaryl, or R₄ and R₅, together with the atoms to which they areattached, form an optionally substituted 5 or 6 membered heterocyclyl.In some embodiments, when R₂ is an optionally substituted C₁-C₄ alkyl orNH(C₁-C₆ alkyl), at least one of R₄ and R₅ is an optionally substitutedcyclopropyl. In some embodiments, when R₂ is an optionally substitutedC₁-C₆ alkyl, R₄ and R₅ are independently selected from an optionallysubstituted C₃-C₆ cycloalkyl. In some embodiments, when R₂ is anoptionally substituted C₁-C₆ alkyl, R₄ is an optionally substitutedC₃-C₆ cycloalkyl and R₅ is an optionally substituted C₁-C₆ alkyl. Insome embodiments, when R₂ is an optionally substituted C₁-C₆ alkyl, R₅is an optionally substituted C₃-C₆ cycloalkyl and R₄ is an optionallysubstituted C₁-C₆ alkyl. In some embodiments, when R₂ is an optionallysubstituted C₁-C₆ alkyl, R₄ and R₅, together with the atoms to whichthey are attached, form an optionally substituted 5 or 6 memberedheterocyclyl, for example, an optionally substituted dioxolane or anoptionally substituted 1,4-dioxane.

In some embodiments, when a C₁-C₆ alkyl, a C₁-C₆ alkoxy, a C₃-C₆cycloalkyl, a C₆-C₁₀ aryl, a 3 to 10 membered heterocyclyl, or a 5 to 10membered heteroaryl is substituted, the substituted substituents areindependently selected from a deuterium, an oxo, a halogen, cyano, anitro, an optionally substituted C₁-C₆ alkyl, an optionally substitutedC₁-C₆ haloalkyl, an optionally substituted C₁-C₆ alkoxy, an optionallysubstituted C₃-C₆ cycloalkyl, an optionally substituted C₆-C₁₀ aryl, anoptionally substituted 3 to 10 membered heterocyclyl, an optionallysubstituted 5 to 10 membered heteroaryl, —C(O)R_(A), —C(O)OR_(A),—C(O)NR_(B)R_(C), —OR_(A), —OC(O)R_(A), —OC(O)NR_(B)R_(C), —OS(O)R_(A),—OS(O)₂R_(A), —OS(O)NR_(B)R_(C), —OS(O)₂NR_(B)R_(C), —NR_(B)R_(C),—NR_(A)C(O)R_(A), —NR_(A)C(O)OR_(A), —NR_(A)C(O)NR_(B)R_(C),—NR_(A)S(O)R_(A), —NR_(A)S(O)₂R_(A), —NR_(A)S(O)NR_(B)R_(C),—NR_(A)S(O)₂NR_(B)R_(C), —SR_(A), —S(O)R_(A), —S(O)₂R_(A),—S(O)NR_(B)R_(C), and —S(O)₂NR_(B)R_(C).

In some embodiments, each R_(A), R_(B), and R_(C) are independentlyselected from a hydrogen, an unsubstituted C₁-C₆ alkyl, an unsubstitutedC₂-C₆ alkenyl, an unsubstituted C₃-C₆ cycloalkyl, an unsubstituted 3 to10 membered heterocyclyl, an unsubstituted C₆-C₁₀ aryl, and anunsubstituted 5 to 10 membered heteroaryl.

In some embodiments, R_(B) and R_(C), together with the nitrogen atom towhich they are attached, form an optionally substituted 3 to 10 memberedheterocyclyl.

In some embodiments, one of X and X₁ is CH₂ and the other is C═O. Insome embodiments, X and X₁ are each CH₂. In some embodiments, X and X₁are each C═O. In some embodiments, one of X and X₁ is CH₂ and the otheris SO. In some embodiments, one of X and X₁ is CH₂ and the other is SO₂.In some embodiments, one of X and X₁ is CH₂ and the other is CH₂CO. Insome embodiments, one of X and X₁ is C═O and the other one of X and X₁is SO. In some embodiments, one of X and X₁ is C═O and the other one ofX and X₁ is SO₂. In some embodiments, one of X and X₁ is C═O and theother is CH₂CO.

In some embodiments, R₁ is —NHR_(1A), —NHC(O)R_(1C) or—NR_(1A)C(O)R_(1C). In some embodiments, R₁ is —NHC(O)R_(1C). In someembodiments, R₁ is —N[C(O)R_(1A)][C(O)R_(1C)]. In some embodiments,R_(1A), R_(1B), and R_(1C) are independently an optionally substitutedC₁-C₆ alkyl or an optionally substituted C₃-C₆ cycloalkyl. In someembodiments, R_(1C) is an optionally substituted C₁-C₆ alkyl. In someembodiments, R_(1C) is an unsubstituted C₁-C₆ alkyl.

In some embodiments, R₃, R₆, and R₇ are independently selected from ahydrogen, a halogen, and an optionally substituted C₁-C₆ alkyl. In someembodiments, R₃, R₆, and R₇ are each hydrogen.

In some embodiments, R₈ is hydrogen or deuterium. In some embodiments,R₈ is hydrogen. In other embodiments, R₈ is deuterium.

In some embodiments, R₂ is an optionally substituted C₁-C₆ alkyl and oneof R₄ and R₅ is an optionally substituted C₁-C₆ alkyl and the other isan optionally substituted C₃-C₆ cycloalkyl or an optionally substituted3 to 10 membered heterocyclyl.

In some embodiments, R₂ is an unsubstituted C₁-C₆ alkyl and one of R₄and R₅ is an unsubstituted C₁-C₆ alkyl and the other is an optionallysubstituted C₃-C₆ cycloalkyl or an optionally substituted 3 to 10membered heterocyclyl.

In some embodiments, R₂ is an optionally substituted C₃-C₆ cycloalkyl,an optionally substituted 3 to 10 membered heterocyclyl, an optionallysubstituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 memberedheteroaryl, and R₄ and R₅ are independently an optionally substitutedC₁-C₆ alkyl.

In some embodiments, R₂ is an optionally substituted C₃-C₆ cycloalkyl,an optionally substituted 3 to 10 membered heterocyclyl, an optionallysubstituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 memberedheteroaryl, and R₄ and R₅ are independently unsubstituted C₁-C₆ alkyl.

In some embodiments, R₄ and R₅, together with the atoms to which theyare attached, form an optionally substituted 5 or 6 memberedheterocyclyl.

In some embodiments, R₄ and R₅, together with the atoms to which theyare attached, form an unsubstituted 5 or 6 membered heterocyclyl.

In some embodiments, R₄ and R₅, together with the atoms to which theyare attached, form an unsubstituted 5 membered heterocyclyl.

In some embodiments, R₄ and R₅, together with the atoms to which theyare attached, form an unsubstituted 6 membered heterocyclyl.

In some embodiments, the compound of Formula (I) is selected from:

or a pharmaceutically acceptable salt of any of the foregoing. In someembodiments of this paragraph, X and X₁ are each independently CH₂, C═O,SO, SO₂, or CH₂CO. In some embodiments of this paragraph, X and X₁ areeach CH₂. In some embodiments of this paragraph, X and X₁ are each C═O.In some embodiments of this paragraph, X and X₁ are each SO. In someembodiments of this paragraph, X and X₁ are each SO₂. In someembodiments of this paragraph, X and X₁ are each CH₂CO. In someembodiments of this paragraph, one of X and X₁ is CH₂ and the other of Xand X₁ is C═O. In some embodiments of this paragraph, one of X and X₁ isCH₂ and the other of X and X₁ is SO. In some embodiments of thisparagraph, one of X and X₁ is CH₂ and the other of X and X₁ is SO₂. Insome embodiments of this paragraph, one of X and X₁ is CH₂ and the otherof X and X₁ is CH₂CO. In some embodiments of this paragraph, one of Xand X₁ is C═O and the other of X and X₁ is SO. In some embodiments ofthis paragraph, one of X and X₁ is C═O and the other of X and X₁ is SO₂.In some embodiments of this paragraph, one of X and X₁ is C═O and theother of X and X₁ is CH₂CO. In some embodiments of this paragraph, R₂ ishydroxy, —NH₂, —NHR_(1A), —NR_(1A)R_(1B), an optionally substitutedC₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionallysubstituted 3 to 10 membered heterocyclyl, an optionally substitutedC₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl.In some embodiments of this paragraph, R₂ is hydroxy. In someembodiments of this paragraph, R₂—NH₂. In some embodiments of thisparagraph, R₂ is an optionally substituted C₁-C₆ alkyl, for example,methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, —CF₃, —CH₂F,—CF₂H, —CD₃, —C(CH₃)₂CF₃, benzyl, or substituted benzyl In someembodiments of this paragraph, R₂ is an optionally substituted C₃-C₆cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In someembodiments of this paragraph, R₂ is an optionally substituted 3 to 10membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine,tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine,thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran,piperazine, morpholine, dioxane. In some embodiments of this paragraph,R₂ is an optionally substituted C₆-C₁₀ aryl, for example, substitutedphenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl. Insome embodiments of this paragraph, R₂ is optionally substituted 5 to 10membered heteroaryl, for example, substituted or unsubstituted furan,furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole,indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine,pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline,cinnoline, or triazine. In some embodiments of this paragraph, R_(1A)and R_(1B) are independently selected from an optionally substitutedC₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionallysubstituted 3 to 10 membered heterocyclyl, an optionally substitutedC₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl.In some embodiments of this paragraph, R₂ is —NHR_(1A), and R_(1A) is anoptionally substituted C₁-C₆ alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl. Insome embodiments of this paragraph, R₂ is —NHR_(1A), and R_(1A) is anoptionally substituted C₃-C₆ cycloalkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or2,2-difluorocyclobutyl. In some embodiments of this paragraph, R₂ is—NHR_(1A), and R_(1A) is an optionally substituted 3 to 10 memberedheterocyclyl, for example, oxetane, azetidine, pyrrolidine,tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine,thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran,piperazine, morpholine, dioxane. In some embodiments of this paragraph,R₂ is —NHR_(1A), and R_(1A) is an optionally substituted C₆-C₁₀ aryl,for example, substituted phenyl, unsubstituted phenyl, naphthyl, orunsubstituted naphthyl. In some embodiments of this paragraph, R₂ is—NHR_(1A), and R_(1A) is an optionally substituted 5 to 10 memberedheteroaryl, for example, substituted or unsubstituted furan, furazan,pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole,benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline,or triazine. In some embodiments of this paragraph, R₂ is—NR_(1A)R_(1B), and R_(1A) and R_(1B) are independently an optionallysubstituted C₁-C₆ alkyl, for example, methyl, ethyl, propyl, isopropyl,butyl, sec-buty, t-butyl, benzyl, or substituted benzyl. In someembodiments of this paragraph, R₂ is —NR_(1A)R_(1B), and R_(1A) andR_(1B) are independently an optionally substituted C₃-C₆ cycloalkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₂ is —NR_(1A)R_(1B), and R_(1A) and R_(1B) areindependently an optionally substituted 3 to 10 membered heterocyclyl,for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran,imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine,morpholine, dioxane. In some embodiments of this paragraph, R₂ is—NR_(1A)R_(1B), and R_(1A) and R_(1B) are independently an optionallysubstituted C₆-C₁₀ aryl, for example, substituted phenyl, unsubstitutedphenyl, naphthyl, or unsubstituted naphthyl. In some embodiments of thisparagraph, R₂ is —NR_(1A)R_(1B), and R_(1A) and R_(1B) are independentlyan optionally substituted 5 to 10 membered heteroaryl, for example,substituted or unsubstituted furan, furazan, pyrrole, oxazole,benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole,benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole,thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, ortriazine. In some embodiments of this paragraph, R₂ is —NR_(1A)R_(1B),one of R_(1A) and R_(1B) is an optionally substituted C₁-C₆ alkyl andthe other of R_(1A) and R_(1B) is an optionally substituted C₆-C₁₀ arylor an optionally substituted 3 to 10 membered heterocyclyl. In someembodiments of this paragraph, R₄ and R₅ are independently selected froman optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, anoptionally substituted C₆-C₁₀ aryl, and an optionally substituted 5 to10 membered heteroaryl. In some embodiments of this paragraph, R₄ andR₅, together with the atoms to which they are attached, form anoptionally substituted 5 or 6 membered heterocyclyl. In some embodimentsof this paragraph, R₄ and R₅ are independently selected from anoptionally substituted C₁-C₆ alkyl. In some embodiments of thisparagraph, R₄ and R₅ are independently selected from an optionallysubstituted C₃-C₆ cycloalkyl. In some embodiments of this paragraph, R₄and R₅ are independently selected from, an optionally substituted 3 to10 membered heterocyclyl. In some embodiments of this paragraph, R₄ andR₅ are independently selected from an optionally substituted C₆-C₁₀aryl. In some embodiments of this paragraph, R₄ and R₅ are independentlyselected from and an optionally substituted 5 to 10 membered heteroaryl.In some embodiments of this paragraph, one of R₄ and R₅ is an optionallysubstituted C₁-C₆ alkyl and the other of R₄ and R₅ is an optionallysubstituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 memberedheterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionallysubstituted 5 to 10 membered heteroaryl. In some embodiments of thisparagraph, one of R₄ and R₅ is an optionally substituted C₁-C₆ alkyl andthe other of R₄ and R₅ is an unsubstituted C₃-C₆ cycloalkyl, anunsubstituted 3 to 10 membered heterocyclyl, an unsubstituted C₆-C₁₀aryl, or an unsubstituted 5 to 10 membered heteroaryl. In someembodiments of this paragraph, one of R₄ and R₅ is an unsubstitutedC₁-C₆ alkyl and the other of R₄ and R₅ is an unsubstituted C₃-C₆cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, anunsubstituted C₆-C₁₀ aryl, or an unsubstituted 5 to 10 memberedheteroaryl. In some embodiments of this paragraph, when R₂ is anoptionally substituted C₁-C₄ alkyl or NH(C₁-C₆ alkyl), at least one ofR₄ and R₅ is an optionally substituted cyclopropyl, an optionallysubstituted 3 to 10 membered heterocyclyl, an optionally substitutedC₆-C₁₀ aryl, an optionally-substituted 5 to 10 membered heteroaryl, orR₄ and R₅, together with the atoms to which they are attached, form anoptionally substituted 5 or 6 membered heterocyclyl.

In some embodiments, the compound of Formula (II) is selected from:

or a pharmaceutically acceptable salt of any of the foregoing. In someembodiments of this paragraph, X and X₁ are each independently CH₂, C═O,SO, SO₂, or CH₂CO. In some embodiments of this paragraph, X and X₁ areeach CH₂. In some embodiments of this paragraph, X and X₁ are each C═O.In some embodiments of this paragraph, X and X₁ are each SO. In someembodiments of this paragraph, X and X₁ are each SO₂. In someembodiments of this paragraph, X and X₁ are each CH₂CO. In someembodiments of this paragraph, one of X and X₁ is CH₂ and the other of Xand X₁ is C═O. In some embodiments of this paragraph, one of X and X₁ isCH₂ and the other of X and X₁ is SO. In some embodiments of thisparagraph, one of X and X₁ is CH₂ and the other of X and X₁ is SO₂. Insome embodiments of this paragraph, one of X and X₁ is CH₂ and the otherof X and X₁ is CH₂CO. In some embodiments of this paragraph, one of Xand X₁ is C═O and the other of X and X₁ is SO. In some embodiments ofthis paragraph, one of X and X₁ is C═O and the other of X and X₁ is SO₂.In some embodiments of this paragraph, one of X and X₁ is C═O and theother of X and X₁ is CH₂CO. In some embodiments of this paragraph, R₂ ishydroxy, —NH₂, —NHR_(1A), —NR_(1A)R_(1B), an optionally substitutedC₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionallysubstituted 3 to 10 membered heterocyclyl, an optionally substitutedC₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl.In some embodiments of this paragraph, R₂ is hydroxy. In someembodiments of this paragraph, R₂—NH₂. In some embodiments of thisparagraph, R₂ is an optionally substituted C₁-C₆ alkyl, for example,methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, —CF₃, —CH₂F,—CF₂H, —CD₃, —C(CH₃)₂CF₃, benzyl, or substituted benzyl In someembodiments of this paragraph, R₂ is an optionally substituted C₃-C₆cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In someembodiments of this paragraph, R₂ is an optionally substituted 3 to 10membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine,tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine,thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran,piperazine, morpholine, dioxane. In some embodiments of this paragraph,R₂ is an optionally substituted C₆-C₁₀ aryl, for example, substitutedphenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl. Insome embodiments of this paragraph, R₂ is optionally substituted 5 to 10membered heteroaryl, for example, substituted or unsubstituted furan,furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole,indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine,pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline,cinnoline, or triazine. In some embodiments of this paragraph, R_(1A)and R_(1B) are independently selected from an optionally substitutedC₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionallysubstituted 3 to 10 membered heterocyclyl, an optionally substitutedC₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl.In some embodiments of this paragraph, R₂ is —NHR_(1A), and R_(1A) is anoptionally substituted C₁-C₆ alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl. Insome embodiments of this paragraph, R₂ is —NHR_(1A), and R_(1A) is anoptionally substituted C₃-C₆ cycloalkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or2,2-difluorocyclobutyl. In some embodiments of this paragraph, R₂ is—NHR_(1A), and R_(1A) is an optionally substituted 3 to 10 memberedheterocyclyl, for example, oxetane, azetidine, pyrrolidine,tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine,thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran,piperazine, morpholine, dioxane. In some embodiments of this paragraph,R₂ is —NHR_(1A), and R_(1A) is an optionally substituted C₆-C₁₀ aryl,for example, substituted phenyl, unsubstituted phenyl, naphthyl, orunsubstituted naphthyl. In some embodiments of this paragraph, R₂ is—NHR_(1A), and R_(1A) is an optionally substituted 5 to 10 memberedheteroaryl, for example, substituted or unsubstituted furan, furazan,pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole,benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline,or triazine. In some embodiments of this paragraph, R₂ is—NR_(1A)R_(1B), and R_(1A) and R_(1B) are independently an optionallysubstituted C₁-C₆ alkyl, for example, methyl, ethyl, propyl, isopropyl,butyl, sec-buty, t-butyl, benzyl, or substituted benzyl. In someembodiments of this paragraph, R₂ is —NR_(1A)R_(1B), and R_(1A) andR_(1B) are independently an optionally substituted C₃-C₆ cycloalkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₂ is —NR_(1A)R_(1B), and R_(1A) and R_(1B) areindependently an optionally substituted 3 to 10 membered heterocyclyl,for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran,imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine,morpholine, dioxane. In some embodiments of this paragraph, R₂ is—NR_(1A)R_(1B), and R_(1A) and R_(1B) are independently an optionallysubstituted C₆-C₁₀ aryl, for example, substituted phenyl, unsubstitutedphenyl, naphthyl, or unsubstituted naphthyl. In some embodiments of thisparagraph, R₂ is —NR_(1A)R_(1B), and R_(1A) and R_(1B) are independentlyan optionally substituted 5 to 10 membered heteroaryl, for example,substituted or unsubstituted furan, furazan, pyrrole, oxazole,benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole,benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole,thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, ortriazine. In some embodiments of this paragraph, R₂ is —NR_(1A)R_(1B),one of R_(1A) and R_(1B) is an optionally substituted C₁-C₆ alkyl andthe other of R_(1A) and R_(1B) is an optionally substituted C₆-C₁₀ arylor an optionally substituted 3 to 10 membered heterocyclyl. In someembodiments of this paragraph, R₄ and R₅ are independently selected froman optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, anoptionally substituted C₆-C₁₀ aryl, and an optionally substituted 5 to10 membered heteroaryl. In some embodiments of this paragraph, R₄ andR₅, together with the atoms to which they are attached, form anoptionally substituted 5 or 6 membered heterocyclyl. In some embodimentsof this paragraph, R₄ and R₅ are independently selected from anoptionally substituted C₁-C₆ alkyl. In some embodiments of thisparagraph, R₄ and R₅ are independently selected from an optionallysubstituted C₃-C₆ cycloalkyl. In some embodiments of this paragraph, R₄and R₅ are independently selected from, an optionally substituted 3 to10 membered heterocyclyl. In some embodiments of this paragraph, R₄ andR₅ are independently selected from an optionally substituted C₆-C₁₀aryl. In some embodiments of this paragraph, R₄ and R₅ are independentlyselected from and an optionally substituted 5 to 10 membered heteroaryl.In some embodiments of this paragraph, one of R₄ and R₅ is an optionallysubstituted C₁-C₆ alkyl and the other of R₄ and R₅ is an optionallysubstituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 memberedheterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionallysubstituted 5 to 10 membered heteroaryl. In some embodiments of thisparagraph, one of R₄ and R₅ is an optionally substituted C₁-C₆ alkyl andthe other of R₄ and R₅ is an unsubstituted C₃-C₆ cycloalkyl, anunsubstituted 3 to 10 membered heterocyclyl, an unsubstituted C₆-C₁₀aryl, or an unsubstituted 5 to 10 membered heteroaryl. In someembodiments of this paragraph, one of R₄ and R₅ is an unsubstitutedC₁-C₆ alkyl and the other of R₄ and R₅ is an unsubstituted C₃-C₆cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, anunsubstituted C₆-C₁₀ aryl, or an unsubstituted 5 to 10 memberedheteroaryl. In some embodiments of this paragraph, when R₂ is anoptionally substituted C₁-C₄ alkyl or NH(C₁-C₆ alkyl), at least one ofR₄ and R₅ is an optionally substituted cyclopropyl, an optionallysubstituted 3 to 10 membered heterocyclyl, an optionally substitutedC₆-C₁₀ aryl, an optionally-substituted 5 to 10 membered heteroaryl, orR₄ and R₅, together with the atoms to which they are attached, form anoptionally substituted 5 or 6 membered heterocyclyl.

In some embodiments, the compound of Formula (I) is selected from:

or a pharmaceutically acceptable salt of any of the foregoing. In someembodiments of this paragraph, R₁ is H, deuterium, hydroxy, halogen,nitro, cyano, optionally substituted C₁-C₆ alkoxy, —NH₂, —NHR_(1A),—NR_(1A)R_(1B), —NHC(O)R_(1C), —NR_(1A)C(O)R_(1C), —NHSO₂R_(1C),—NR_(1A)SO₂R_(1C), —N[C(O)R_(1A)][C(O)R_(1C)]. an optionally substitutedC₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionallysubstituted 3 to 10 membered heterocyclyl, an optionally substitutedC₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl.In some embodiments of this paragraph, R_(1A), R_(1B), and R_(1C) areindependently selected from an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or anoptionally substituted 5 to 10 membered heteroaryl. In some embodimentsof this paragraph, R₁ is H. In some embodiments of this paragraph, R₁ ishydroxy. In some embodiments of this paragraph, R₁ is nitro. In someembodiments of this paragraph, R₁ is cyano. In some embodiments of thisparagraph, R₁ is halogen, for example, fluoro, chloro, or bromo. In someembodiments of this paragraph, R₁ is optionally substituted C₁-C₆alkoxy, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,sec-butoxy, t-butoxy, —OCF₃, or —OCD₃. In some embodiments of thisparagraph, R₁ is an optionally substituted C₁-C₆ alkyl, for example,methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, —CF₃, —CH₂F,—CF₂H, —CD₃, —C(CH₃)₂CF₃, benzyl, or substituted benzyl In someembodiments of this paragraph, R₁ is —NH₂. In some embodiments of thisparagraph, R₁ is an optionally substituted C₃-C₆ cycloalkyl, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₁ is an optionally substituted 3 to 10 memberedheterocyclyl, for example, oxetane, azetidine, pyrrolidine,tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine,thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran,piperazine, morpholine, dioxane. In some embodiments of this paragraph,R₁ is an optionally substituted C₆-C₁₀ aryl, for example, substitutedphenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl. Insome embodiments of this paragraph, R₁ is optionally substituted 5 to 10membered heteroaryl, for example, substituted or unsubstituted furan,furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole,indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine,pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline,cinnoline, or triazine. In some embodiments of this paragraph, R₁ is—NHR_(1A), and R_(1A) is an optionally substituted C₁-C₆ alkyl, forexample, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl,benzyl, or substituted benzyl. In some embodiments of this paragraph, R₁is —NHR_(1A), and R_(1A) is an optionally substituted C₃-C₆ cycloalkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₁ is —NHR_(1A), and R_(1A) is an optionallysubstituted 3 to 10 membered heterocyclyl, for example, oxetane,azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane,piperidine, tetrahydropyran, piperazine, morpholine, dioxane. In someembodiments of this paragraph, R₁ is —NHR_(1A), and R_(1A) is anoptionally substituted C₆-C₁₀ aryl, for example, substituted phenyl,unsubstituted phenyl, naphthyl, or unsubstituted naphthyl. In someembodiments of this paragraph, R₁ is —NHR_(1A), and R_(1A) is anoptionally substituted 5 to 10 membered heteroaryl, for example,substituted or unsubstituted furan, furazan, pyrrole, oxazole,benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole,benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole,thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, ortriazine. In some embodiments of this paragraph, R₁ is —NR_(1A)R_(1B),and R_(1A) and R_(1B) are independently an optionally substituted C₁-C₆alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty,t-butyl, benzyl, or substituted benzyl. In some embodiments of thisparagraph, R₁ is —NR_(1A)R_(1B), and R_(1A) and R_(1B) are independentlyan optionally substituted C₃-C₆ cycloalkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or2,2-difluorocyclobutyl. In some embodiments of this paragraph, R₁ is—NR_(1A)R_(1B), and R_(1A) and R_(1B) are independently an optionallysubstituted 3 to 10 membered heterocyclyl, for example, oxetane,azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane,piperidine, tetrahydropyran, piperazine, morpholine, dioxane. In someembodiments of this paragraph, R₁ is —NR_(1A)R_(1B), and R_(1A) andR_(1B) are independently an optionally substituted C₆-C₁₀ aryl, forexample, substituted phenyl, unsubstituted phenyl, naphthyl, orunsubstituted naphthyl. In some embodiments of this paragraph, R₁ is—NR_(1A)R_(1B), and R_(1A) and R_(1B) are independently an optionallysubstituted 5 to 10 membered heteroaryl, for example, substituted orunsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole,benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole,benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole,pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline,quinazoline, quinoxaline, cinnoline, or triazine. In some embodiments ofthis paragraph, R₁ is —NR_(1A)R_(1B), one of R_(1A) and R_(1B) is anoptionally substituted C₁-C₆ alkyl and the other of R_(1A) and R_(1B) isan optionally substituted C₆-C₁₀ aryl or an optionally substituted 3 to10 membered heterocyclyl. In some embodiments of this paragraph, R₁ is—NHC(O)R_(1C), and R_(1C) is an optionally substituted C₁-C₆ alkyl, forexample, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl,benzyl, or substituted benzyl. In some embodiments of this paragraph, R₁is —NHC(O)R_(1C), and R_(1C) is an optionally substituted C₃-C₆cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₁ is —NHC(O)R_(1C), and R_(1C) is an optionallysubstituted 3 to 10 membered heterocyclyl, for example, oxetane,azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane,piperidine, tetrahydropyran, piperazine, morpholine, dioxane. In someembodiments of this paragraph, R₁ is —NHC(O)R_(1C), and R_(1C) is anoptionally substituted C₆-C₁₀ aryl, for example, substituted phenyl,unsubstituted phenyl, naphthyl, or unsubstituted naphthyl. In someembodiments of this paragraph, R₁ is —NHC(O)R_(1C), and R_(1C) is anoptionally substituted 5 to 10 membered heteroaryl, for example,substituted or unsubstituted furan, furazan, pyrrole, oxazole,benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole,benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole,thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, ortriazine. In some embodiments of this paragraph, R₁ is —NHSO₂R_(1C), andR_(1C) is an optionally substituted C₁-C₆ alkyl, for example, methyl,ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, benzyl, orsubstituted benzyl. In some embodiments of this paragraph, R₁ is—NHSO₂R_(1C), and R_(1C) is an optionally substituted C₃-C₆ cycloalkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₁ is —N[C(O)R_(1A)][C(O)R_(1C)], and R_(1A) andR_(1C) are independently an optionally substituted C₁-C₆ alkyl, forexample, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl,benzyl, or substituted benzyl. In some embodiments of this paragraph, R₁is —NHSO₂R_(1C), and R_(1C) is an optionally substituted 3 to 10membered heterocyclyl, for example, oxetane, azetidine, pyrrolidine,tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine,thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran,piperazine, morpholine, dioxane. In some embodiments of this paragraph,R₁ is —NHSO₂R_(1C), and R_(1C) is an optionally substituted C₆-C₁₀ aryl,for example, substituted phenyl, unsubstituted phenyl, naphthyl, orunsubstituted naphthyl. In some embodiments of this paragraph, R₁ is—NHSO₂R_(1C), and R_(1C) is an optionally substituted 5 to 10 memberedheteroaryl, for example, substituted or unsubstituted furan, furazan,pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole,benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline,or triazine. In some embodiments of this paragraph, R₁ is—NR_(1A)C(O)R_(1C), and R_(1A) and R_(1C) are independently anoptionally substituted C₁-C₆ alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl. Insome embodiments of this paragraph, R₁ is —NR_(1A)C(O)R_(1C), and R_(1A)and R_(1C) are independently an optionally substituted C₃-C₆ cycloalkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₁ is —NR_(1A)C(O)R_(1C), and R_(1A) and R_(1C) areindependently an optionally substituted 3 to 10 membered heterocyclyl,for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran,imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine,morpholine, dioxane. In some embodiments of this paragraph, R₁ is—NR_(1A)C(O)R_(1C), and R_(1A) and R_(1C) are independently anoptionally substituted C₆-C₁₀ aryl, for example, substituted phenyl,unsubstituted phenyl, naphthyl, or unsubstituted naphthyl. In someembodiments of this paragraph, R₁ is —NR_(1A)C(O)R_(1C), and R_(1A) andR_(1C) are independently an optionally substituted 5 to 10 memberedheteroaryl, for example, substituted or unsubstituted furan, furazan,pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole,benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline,or triazine. In some embodiments of this paragraph, R₁ is—NR_(1A)C(O)R_(1C), one of R_(1A) and R_(1C) is an optionallysubstituted C₁-C₆ alkyl and the other of R_(1A) and R_(1C) is anoptionally substituted C₆-C₁₀ aryl or an optionally substituted 3 to 10membered heterocyclyl. In some embodiments of this paragraph, R₁ is—NR_(1A)SO₂R_(1C), and R_(1A) and R_(1C) are independently an optionallysubstituted C₁-C₆ alkyl, for example, methyl, ethyl, propyl, isopropyl,butyl, sec-buty, t-butyl, benzyl, or substituted benzyl. In someembodiments of this paragraph, R₁ is —NR_(1A)SO₂R_(1C), and R_(1A) andR_(1C) are independently an optionally substituted C₃-C₆ cycloalkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₁ is —NR_(1A)SO₂R_(1C), and R_(1A) and R_(1C) areindependently an optionally substituted 3 to 10 membered heterocyclyl,for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran,imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine,morpholine, dioxane. In some embodiments of this paragraph, R₁ is—NR_(1A)SO₂R_(1C), and R_(1A) and R_(1C) are independently an optionallysubstituted C₆-C₁₀ aryl, for example, substituted phenyl, unsubstitutedphenyl, naphthyl, or unsubstituted naphthyl. In some embodiments of thisparagraph, R₁ is —NR_(1A)SO₂R_(1C), and R_(1A) and R_(1C) areindependently an optionally substituted 5 to 10 membered heteroaryl, forexample, substituted or unsubstituted furan, furazan, pyrrole, oxazole,benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole,benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole,thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, ortriazine. In some embodiments of this paragraph, R₁ is—NR_(1A)SO₂R_(1C), one of R_(1A) and R_(1C) is an optionally substitutedC₁-C₆ alkyl and the other of R_(1A) and R_(1C) is an optionallysubstituted C₆-C₁₀ aryl or an optionally substituted 3 to 10 memberedheterocyclyl.

In some embodiments, the compound of Formula (II) is selected from:

or a pharmaceutically acceptable salt of any of the foregoing. In someembodiments of this paragraph, R₁ is H, deuterium, hydroxy, halogen,nitro, cyano, optionally substituted C₁-C₆ alkoxy, —NH₂, —NHR_(1A),—NR_(1A)R_(1B), —NHC(O)R_(1C), —NR_(1A)C(O)R_(1C), —NHSO₂R_(1C),—NR_(1A)SO₂R_(1C), —N[C(O)R_(1A)][C(O)R_(1C)], an optionally substitutedC₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionallysubstituted 3 to 10 membered heterocyclyl, an optionally substitutedC₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl.In some embodiments of this paragraph, R_(1A), R_(1B), and R_(1C) areindependently selected from an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or anoptionally substituted 5 to 10 membered heteroaryl. In some embodimentsof this paragraph, R₁ is H. In some embodiments of this paragraph, R₁ ishydroxy. In some embodiments of this paragraph, R₁ is nitro. In someembodiments of this paragraph, R₁ is cyano. In some embodiments of thisparagraph, R₁ is halogen, for example, fluoro, chloro, or bromo. In someembodiments of this paragraph, R₁ is optionally substituted C₁-C₆alkoxy, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,sec-butoxy, t-butoxy, —OCF₃, or —OCD₃. In some embodiments of thisparagraph, R₁ is an optionally substituted C₁-C₆ alkyl, for example,methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl, —CF₃, —CH₂F,—CF₂H, —CD₃, —C(CH₃)₂CF₃, benzyl, or substituted benzyl In someembodiments of this paragraph, R₁ is —NH₂. In some embodiments of thisparagraph, R₁ is an optionally substituted C₃-C₆ cycloalkyl, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₁ is an optionally substituted 3 to 10 memberedheterocyclyl, for example, oxetane, azetidine, pyrrolidine,tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine,thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran,piperazine, morpholine, dioxane. In some embodiments of this paragraph,R₁ is an optionally substituted C₆-C₁₀ aryl, for example, substitutedphenyl, unsubstituted phenyl, naphthyl, or unsubstituted naphthyl. Insome embodiments of this paragraph, R₁ is optionally substituted 5 to 10membered heteroaryl, for example, substituted or unsubstituted furan,furazan, pyrrole, oxazole, benzoxazole, imidazole, benzimidazole,indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole,triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine,pyrimidine, pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline,cinnoline, or triazine. In some embodiments of this paragraph, R₁ is—NHR_(1A), and R_(1A) is an optionally substituted C₁-C₆ alkyl, forexample, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl,benzyl, or substituted benzyl. In some embodiments of this paragraph, R₁is —NHR_(1A), and R_(1A) is an optionally substituted C₃-C₆ cycloalkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₁ is —NHR_(1A), and R_(1A) is an optionallysubstituted 3 to 10 membered heterocyclyl, for example, oxetane,azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane,piperidine, tetrahydropyran, piperazine, morpholine, dioxane. In someembodiments of this paragraph, R₁ is —NHR_(1A), and R_(1A) is anoptionally substituted C₆-C₁₀ aryl, for example, substituted phenyl,unsubstituted phenyl, naphthyl, or unsubstituted naphthyl. In someembodiments of this paragraph, R₁ is —NHR_(1A), and R_(1A) is anoptionally substituted 5 to 10 membered heteroaryl, for example,substituted or unsubstituted furan, furazan, pyrrole, oxazole,benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole,benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole,thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, ortriazine. In some embodiments of this paragraph, R₁ is —NR_(1A)R_(1B),and R_(1A) and R_(1B) are independently an optionally substituted C₁-C₆alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-buty,t-butyl, benzyl, or substituted benzyl. In some embodiments of thisparagraph, R₁ is —NR_(1A)R_(1B), and R_(1A) and R_(1B) are independentlyan optionally substituted C₃-C₆ cycloalkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or2,2-difluorocyclobutyl. In some embodiments of this paragraph, R₁ is—NR_(1A)R_(1B), and R_(1A) and R_(1B) are independently an optionallysubstituted 3 to 10 membered heterocyclyl, for example, oxetane,azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane,piperidine, tetrahydropyran, piperazine, morpholine, dioxane. In someembodiments of this paragraph, R₁ is —NR_(1A)R_(1B), and R_(1A) andR_(1B) are independently an optionally substituted C₆-C₁₀ aryl, forexample, substituted phenyl, unsubstituted phenyl, naphthyl, orunsubstituted naphthyl. In some embodiments of this paragraph, R₁ is—NR_(1A)R_(1B), and R_(1A) and R_(1B) are independently an optionallysubstituted 5 to 10 membered heteroaryl, for example, substituted orunsubstituted furan, furazan, pyrrole, oxazole, benzoxazole, imidazole,benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole,benzoisoxazole, triazole, benzotriazole, thiadiazole, tetrazole,pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinoline,quinazoline, quinoxaline, cinnoline, or triazine. In some embodiments ofthis paragraph, R₁ is —NR_(1A)R_(1B), one of R_(1A) and R_(1B) is anoptionally substituted C₁-C₆ alkyl and the other of R_(1A) and R_(1B) isan optionally substituted C₆-C₁₀ aryl or an optionally substituted 3 to10 membered heterocyclyl. In some embodiments of this paragraph, R₁ is—NHC(O)R_(1C), and R_(1C) is an optionally substituted C₁-C₆ alkyl, forexample, methyl, ethyl, propyl, isopropyl, butyl, sec-buty, t-butyl,benzyl, or substituted benzyl. In some embodiments of this paragraph, R₁is —NHC(O)R_(1C), and R_(1C) is an optionally substituted C₃-C₆cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₁ is —NHC(O)R_(1C), and R_(1C) is an optionallysubstituted 3 to 10 membered heterocyclyl, for example, oxetane,azetidine, pyrrolidine, tetrahydrofuran, imidazoline, pyrazolidine,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane,piperidine, tetrahydropyran, piperazine, morpholine, dioxane. In someembodiments of this paragraph, R₁ is —NHC(O)R_(1C), and R_(1C) is anoptionally substituted C₆-C₁₀ aryl, for example, substituted phenyl,unsubstituted phenyl, naphthyl, or unsubstituted naphthyl. In someembodiments of this paragraph, R₁ is —NHC(O)R_(1C), and R_(1C) is anoptionally substituted 5 to 10 membered heteroaryl, for example,substituted or unsubstituted furan, furazan, pyrrole, oxazole,benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole,benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole,thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, ortriazine. In some embodiments of this paragraph, R₁ is—N[C(O)R_(1A)][C(O)R_(1C)], and R_(1A) and R_(1C) are independently anoptionally substituted C₁-C₆ alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl. Insome embodiments of this paragraph, R₁ is —NHSO₂R_(1C), and R_(1C) is anoptionally substituted C₁-C₆ alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl. Insome embodiments of this paragraph, R₁ is —NHSO₂R_(1C), and R_(1C) is anoptionally substituted C₃-C₆ cycloalkyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2,2-difluorocyclopropyl, or2,2-difluorocyclobutyl. In some embodiments of this paragraph, R₁ is—NHSO₂R_(1C), and R_(1C) is an optionally substituted 3 to 10 memberedheterocyclyl, for example, oxetane, azetidine, pyrrolidine,tetrahydrofuran, imidazoline, pyrazolidine, oxazolidine, isoxazolidine,thiazolidine, isothiazolidine, dioxolane, piperidine, tetrahydropyran,piperazine, morpholine, dioxane. In some embodiments of this paragraph,R₁ is —NHSO₂R_(1C), and R_(1C) is an optionally substituted C₆-C₁₀ aryl,for example, substituted phenyl, unsubstituted phenyl, naphthyl, orunsubstituted naphthyl. In some embodiments of this paragraph, R₁ is—NHSO₂R_(1C), and R_(1C) is an optionally substituted 5 to 10 memberedheteroaryl, for example, substituted or unsubstituted furan, furazan,pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole,benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline,or triazine. In some embodiments of this paragraph, R₁ is—NR_(1A)C(O)R_(1C), and R_(1A) and R_(1C) are independently anoptionally substituted C₁-C₆ alkyl, for example, methyl, ethyl, propyl,isopropyl, butyl, sec-buty, t-butyl, benzyl, or substituted benzyl. Insome embodiments of this paragraph, R₁ is —NR_(1A)C(O)R_(1C), and R_(1A)and R_(1C) are independently an optionally substituted C₃-C₆ cycloalkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₁ is —NR_(1A)C(O)R_(1C), and R_(1A) and R_(1C) areindependently an optionally substituted 3 to 10 membered heterocyclyl,for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran,imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine,morpholine, dioxane. In some embodiments of this paragraph, R₁ is—NR_(1A)C(O)R_(1C), and R_(1A) and R_(1C) are independently anoptionally substituted C₆-C₁₀ aryl, for example, substituted phenyl,unsubstituted phenyl, naphthyl, or unsubstituted naphthyl. In someembodiments of this paragraph, R₁ is —NR_(1A)C(O)R_(1C), and R_(1A) andR_(1C) are independently an optionally substituted 5 to 10 memberedheteroaryl, for example, substituted or unsubstituted furan, furazan,pyrrole, oxazole, benzoxazole, imidazole, benzimidazole, indole,indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, triazole,benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine,pyrazine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline,or triazine. In some embodiments of this paragraph, R₁ is—NR_(1A)C(O)R_(1C), one of R_(1A) and R_(1C) is an optionallysubstituted C₁-C₆ alkyl and the other of R_(1A) and R_(1C) is anoptionally substituted C₆-C₁₀ aryl or an optionally substituted 3 to 10membered heterocyclyl. In some embodiments of this paragraph, R₁ is—NR_(1A)SO₂R_(1C), and R_(1A) and R_(1C) are independently an optionallysubstituted C₁-C₆ alkyl, for example, methyl, ethyl, propyl, isopropyl,butyl, sec-buty, t-butyl, benzyl, or substituted benzyl. In someembodiments of this paragraph, R₁ is —NR_(1A)SO₂R_(1C), and R_(1A) andR_(1C) are independently an optionally substituted C₃-C₆ cycloalkyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2,2-difluorocyclopropyl, or 2,2-difluorocyclobutyl. In some embodimentsof this paragraph, R₁ is —NR_(1A)SO₂R_(1C), and R_(1A) and R_(1C) areindependently an optionally substituted 3 to 10 membered heterocyclyl,for example, oxetane, azetidine, pyrrolidine, tetrahydrofuran,imidazoline, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine,isothiazolidine, dioxolane, piperidine, tetrahydropyran, piperazine,morpholine, dioxane. In some embodiments of this paragraph, R₁ is—NR_(1A)SO₂R_(1C), and R_(1A) and R_(1C) are independently an optionallysubstituted C₆-C₁₀ aryl, for example, substituted phenyl, unsubstitutedphenyl, naphthyl, or unsubstituted naphthyl. In some embodiments of thisparagraph, R₁ is —NR_(1A)SO₂R_(1C), and R_(1A) and R_(1C) areindependently an optionally substituted 5 to 10 membered heteroaryl, forexample, substituted or unsubstituted furan, furazan, pyrrole, oxazole,benzoxazole, imidazole, benzimidazole, indole, indazole, pyrazole,benzopyrazole, isoxazole, benzoisoxazole, triazole, benzotriazole,thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, ortriazine. In some embodiments of this paragraph, R₁ is—NR_(1A)SO₂R_(1C), one of R_(1A) and R_(1C) is an optionally substitutedC₁-C₆ alkyl and the other of R_(1A) and R_(1C) is an optionallysubstituted C₆-C₁₀ aryl or an optionally substituted 3 to 10 memberedheterocyclyl.

In some embodiments, the compound is a pharmaceutically acceptable salt.

One or more of the compounds of preferred embodiments can be provided inthe form of pharmaceutically acceptable salts, solvates, activemetabolites, tautomers, or prodrugs thereof. Some embodiments can beprovided in pharmaceutical compositions comprising a therapeuticallyeffective amount of the compound. In some embodiments, thepharmaceutical composition also contains at least one pharmaceuticallyacceptable inactive ingredient. The pharmaceutical composition can beformulated for intravenous injection, subcutaneous injection, oraladministration, buccal administration, inhalation, nasal administration,topical administration, transdermal administration, ophthalmicadministration, or optic administration. The pharmaceutical compositioncan be in the form of a tablet, a pill, a capsule, a liquid, aninhalant, a nasal spray solution, a suppository, a suspension, a gel, acolloid, a dispersion, a solution, an emulsion, an ointment, a lotion,an eye drop, or an ear drop.

In some embodiments, the pharmaceutical composition is formulated as agel, salve, ointment, cream, emulsion, or paste for topical applicationto the skin.

The pharmaceutical compositions of preferred embodiments can furthercomprise one or more additional therapeutically active agents other thana compound of the preferred embodiments. Such agents can include, butare not limited to, anti-inflammatory agents, anti-cancer agents,immunostimulatory agents, and immunosuppressive agents.

Some embodiments provide a method of treating, ameliorating, orpreventing a disease, disorder, or condition associated with PDE4,comprising administering a therapeutically effective amount of acompound of any one of Formula (I), Formula (II), or a pharmaceuticallyacceptable salt of any of the foregoing, or a composition comprising anyone of Formula (I) or Formula (II) to a subject in need thereof.

In some embodiments, the disease, disorder, or condition is selectedfrom the group consisting of arthritis, ankylosing spondylitis,osteoarthritis, rheumatoid arthritis, Behcet's disease, inflammatorybowel diseases (e.g., Crohn's disease and ulcerative colitis),psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis,and combinations thereof. In some embodiments, the disease, disorder, orcondition is arthritis. In some embodiments, the disease, disorder, orcondition is ankylosing spondylitis. In some embodiments, the disease,disorder, or condition is osteoarthritis. In some embodiments, thedisease, disorder, or condition is rheumatoid arthritis. In someembodiments, the disease, disorder, or condition is Behcet's disease. Insome embodiments, the disease, disorder, or condition is Crohn'sdisease. In some embodiments, the disease, disorder, or condition isulcerative colitis. In some embodiments, the disease, disorder, orcondition is psoriasis. In some embodiments, the disease, disorder, orcondition is psoriatic arthritis. In some embodiments, the disease,disorder, or condition is atopic dermatitis. In some embodiments, thedisease, disorder, or condition is contact dermatitis. In someembodiments, the disease, disorder, or condition is selected from two ofarthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis,Behcet's disease, inflammatory bowel diseases (e.g., Crohn's disease andulcerative colitis), psoriasis, psoriatic arthritis, atopic dermatitis,and contact dermatitis.

In some embodiments, the compound or composition is administered incombination with a second therapeutic agent. In some embodiments, thesecond therapeutic agent is selected from the group consisting ofanti-inflammatory agents, anti-cancer agents, immunostimulatory agents,and immunosuppressive agents. In some embodiments, the secondtherapeutic agent is an anti-inflammatory agent or an immunosuppressiveagent.

Some embodiments provide a method of decreasing expression of a proteinselected from TNF-α, INF-γ, IL-2, IL-17, IL-23, or a combinationthereof, comprising contacting a cell with a compound of any one ofFormula (I) or Formula (II), or a pharmaceutically acceptable salt ofany of the foregoing. In some embodiments, the protein is TNF-α. Someembodiments provide a method of decreasing expression of TNF-α. Someembodiments provide a method of decreasing expression of INF-γ. Someembodiments provide a method of decreasing expression of IL-2. Someembodiments provide a method of decreasing expression of IL-17. Someembodiments provide a method of decreasing expression of IL-23. Someembodiments provide a method of decreasing expression of two proteinsselected from TNF-α, INF-γ, IL-2, IL-17, and IL-23. Some embodimentsprovide a method of decreasing expression of three proteins selectedfrom TNF-α, INF-γ, IL-2, IL-17, and IL-23. Some embodiments provide amethod of decreasing expression of four proteins selected from TNF-α,INF-γ, IL-2, IL-17, and IL-23. Some embodiments provide a method ofdecreasing expression of TNF-α, INF-γ, IL-2, IL-17, and IL-23.

In some embodiments, protein expression is decreased by about 10% toabout 90%, about 5% to about 25%, about 20% to about 40%, about 35% toabout 55%, about 50% to about 75%, about 70% to about 90%, or any valuein between. In some embodiments, protein expression is decreased byabout 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%,33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%,47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%,61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%,75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or any value inbetween.

Some embodiments provide a method of inhibiting PDE4 activity,comprising contacting a cell with a compound of any one of Formula (I)or Formula (II), or a pharmaceutically acceptable salt of any of theforegoing. In some embodiments, PDE4 activity is decreased by about 10%to about 90%, about 5% to about 25%, about 20% to about 40%, about 35%to about 55%, about 50% to about 75%, about 70% to about 90%, or anyvalue in between. In some embodiments, protein expression is decreasedby about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%,18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%,32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%,46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%,60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%,74%, 74%, 75%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or any valuein between.

Some embodiments provide a method of treating psoriasis, comprisingtopically administering a therapeutically effective amount of acomposition comprising any one of Formula (I) or Formula (II), or apharmaceutically acceptable salt of any of the foregoing, to a subjectin need thereof.

In some embodiments, the subject is known to possess wild-type PDE4. Insome embodiments, the subject is known to possess wild-type TNF-α. Insome embodiments, the subject is known to possess wild-type INF-γ, IL-2,IL-17, or IL-23. In some embodiments, the subject is known to possessaberrant PDE4. In some embodiments, the subject is known to possessaberrant TNF-α. In some embodiments, the subject is known to possessaberrant INF-γ, IL-2, IL-17, or IL-23.

In some embodiments, the cell is known to possess wild-type PDE4. Insome embodiments, the cell is known to possess wild-type TNF-α. In someembodiments, the cell is known to possess wild-type INF-γ, IL-2, IL-17,or IL-23. In some embodiments, the cell is known to possess aberrantPDE4. In some embodiments, the cell is known to possess aberrant TNF-α.In some embodiments, the cell is known to possess aberrant INF-γ, IL-2,IL-17, or IL-23.

Other objects, features, and advantages of the compounds, methods, andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

Additional Therapeutic Agents

Some embodiments provide pharmaceutical compositions comprising acompound of Formula (I) or Formula (II), and a pharmaceuticallyacceptable carrier. Some embodiments provide pharmaceutical compositionscomprising of Formula (I) or Formula (II) a pharmaceutically acceptablecarrier, and a second therapeutic agent.

In some embodiments, the second therapeutic agent is anti-inflammatoryagent. In some embodiments, the second therapeutic agent is anon-steroidal anti-inflammatory agent. In some embodiments, the secondtherapeutic agent is anti-cancer agent. In some embodiments, the secondtherapeutic agent is an immunostimulatory agent. In some embodiments,the second therapeutic agent is an immunosuppressive agent. In someembodiments, the second therapeutic agent is antibody.

In some embodiments, the second therapeutic agent is selected fromaspirin; diflunisal; salsalate; acetaminophen; ibuprofen; dexibuprofen;naproxen; fenoprofen; ketoprofen; dexketoprofen; flurbiprofen;oxaprozin; loxoprofen; indomethacin; tolmetin; sulindac; etodolac;ketorolac; diclofenac; aceclofenac; nabumetone; enolic acid; piroxicam;meloxicam; tenoxicam; droxicam; lornoxicam; isoxicam; mefenamic acid;meclofenamic acid; flufenamic acid; tolfenamic acid; sulfonanilides;clonixin; licofelone; dexamethasone; and prednisone.

In some embodiments, the second therapeutic agent is selected frommechlorethamine; cyclophosphamide; melphalan; chlorambucil; ifosfamide;busulfan; N-nitroso-N-methylurea (MNU); carmustine (BCNU); lomustine(CCNU); semustine (MeCCNU); fotemustine; streptozotocin; dacarbazine;mitozolomide; temozolomide; thiotepa; mytomycin; diaziquone (AZQ);cisplatin; carboplatin; and oxaliplatin.

In some embodiments, the second therapeutic agent is selected fromvincristine; vinblastine; vinorelbine; vindesine; vinflunine;paclitaxel; docetaxel; etoposide; teniposide; tofacitinib; ixabepilone;irinotecan; topotecan; camptothecin; doxorubicin; mitoxantrone; andteniposide.

In some embodiments, the second therapeutic agent is selected fromactinomycin; bleomycin; plicamycin; mitomycin; daunorubicin; epirubicin;idarubicin; pirarubicin; aclarubicin; mitoxantrone; cyclophosphamide;methotrexate; 5-fluorouracil; prednisolone; folinic acid; methotrexate;melphalan; capecitabine; mechlorethamine; uramustine; melphalan;chlorambucil; ifosfamide; bendamustine; 6-mercaptopurine; andprocarbazine.

In some embodiments, the second therapeutic agent is selected fromcladribine; pemetrexed; fludarabine; gemcitabine; hydroxyurea;nelarabine; cladribine; clofarabine; ytarabine; decitabine; cytarabine;cytarabine liposomal; pralatrexate; floxuridine; fludarabine;colchicine; thioguanine; cabazitaxel; larotaxel; ortataxel; tesetaxel;aminopterin; pemetrexed; pralatrexate; raltitrexed; pemetrexed;carmofur; and floxuridine.

In some embodiments, the second therapeutic agent is selected fromazacitidine; decitabine; hydroxycarbamide; topotecan; irinotecan;belotecan; teniposide; aclarubicin; epirubicin; idarubicin; amrubicin;pirarubicin; valrubicin; zorubicin; mitoxantrone; pixantrone;mechlorethamine; chlorambucil; prednimustine; uramustine; estramustine;carmustine; lomustine; fotemustine; nimustine; ranimustine; carboquone;thioTEPA; triaziquone; and triethylenemelamine.

In some embodiments, the second therapeutic agent is selected fromnedaplatin; satraplatin; procarbazine; dacarbazine; temozolomide;altretamine; mitobronitol; pipobroman; actinomycin; bleomycin;plicamycin; aminolevulinic acid; methyl aminolevulinate; efaproxiral;talaporfin; temoporfin; verteporfin; alvocidib; seliciclib; palbociclib;bortezomib; carfilzomib; anagrelide; masoprocol; olaparib; belinostat;panobinostat; romidepsin; vorinosta; idelalisib; atrasentan; bexarotene;testolactone; amsacrine; trabectedin; alitretinoin; tretinoin;demecolcine; elsamitrucin; etoglucid; lonidamine; lucanthone;mitoguazone; mitotane; oblimersen; omacetaxine mepesuccinate; anderibulin.

In some embodiments, the second therapeutic agent is selected fromazathioprine; Mycophenolic acid; leflunomide; teriflunomide; tacrolimus;cyclosporin; pimecrolimus; abetimus; gusperimus; lenalidomide;pomalidomide; thalidomide; anakinra; sirolimus; everolimus;ridaforolimus; temsirolimus; umirolimus; zotarolimus; eculizumab;adalimumab; afelimomab; certolizumab pegol; golimumab; infliximab;nerelimomab; mepolizumab; omalizumab; faralimomab; elsilimomab;lebrikizumab; ustekinumab; etanercept; otelixizumab; teplizumab;visilizumab; clenoliximab; keliximab; zanolimumab; efalizumab;erlizumab; obinutuzumab; rituximab; and ocrelizumab.

In some embodiments, the second therapeutic agent is selected frompascolizumab; gomiliximab; lumiliximab; teneliximab; toralizumab;aselizumab; galiximab; gavilimomab; ruplizumab; belimumab; blisibimod;ipilimumab; tremelimumab; bertilimumab; lerdelimumab; metelimumab;natalizumab; tocilizumab; odulimomab; basiliximab; daclizumab;inolimomab; zolimoma; atorolimumab; cedelizumab; fontolizumab;maslimomab; morolimumab; pexelizumab; reslizumab; rovelizumab;siplizumab; talizumab; telimomab; vapaliximab; vepalimomab; abatacept;belatacept; pegsunercept; aflibercept; alefacept; and rilonacept.

Dosing Regimes

In some embodiments, about 1 mg to about 5 grams; 2 mg to 2 gram; 5 mgto about 1 gram; 10 mg to about 800 mg; 20 mg to 600 mg; 30 mg to 400mg; 40 mg to 200 mg; 50 mg to 100 mg of a compound of Formula (I),Formula (II), or any amount in between, is administered each day. Insome embodiments, about 1 mg to about 5 grams; 2 mg to 2 gram; 5 mg toabout 1 gram; 10 mg to about 800 mg; 20 mg to 600 mg; 30 mg to 400 mg;40 mg to 200 mg; 50 mg to 100 mg of a compound of Formula (I), Formula(II), or any amount in between, is administered each week. In someembodiments, about 1 mg to about 5 grams; 2 mg to 2 gram; 5 mg to about1 gram; 10 mg to about 800 mg; 20 mg to 600 mg; 30 mg to 400 mg; 40 mgto 200 mg; 50 mg to 100 mg of a compound of Formula (I), Formula (II),or any amount in between, is administered each cycle of treatment.

In some embodiments, a compound of Formula (I) or Formula (II) isadministered at least once per day, at least twice per day, at leastthree times per day, or at least four times per day. In someembodiments, a compound of Formula (I) or Formula (II) is administeredat least once per day, at least twice per day, at least three times perday, or at least four times per week. In some embodiments, each cycle oftreatment lasts 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days,or any value in between. In some embodiments, each cycle of treatmenthas at least 1, 2, 3, 4, 5, 6, or 7 days between administrations of acompound of Formula (I), Formula (II), or any value in between.

In some embodiments, a compound of Formula (I) or Formula (II) isprovided intravenously over about 10, 20, 30, 40, 50, 60, 90, 120, 150,180, 210, or 240 minutes, or any value in between.

EXAMPLES

Additional embodiments are disclosed in further detail in the followingexamples, which are not in any way intended to limit the scope of theclaims.

Characterization of the compounds disclosed herein was performed withBruker AV-500 and Bruker DRX-500 NMR spectrometers and a Perkin ElmerPE-SCIEX API-150 mass spectrometer.

Synthesis

Example 1: Compound 1:(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide

A solution of(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(40 mg, 0.094 mmol) in pyridine (4 mL) was cooled to 0° C. then acetylchloride (0.15 mL in 1 mL DCM) was added. The mixture was stirred at 0 Cfor 0.5 h. HCl (2 M, 3 mL) was added and the organic layer wasseparated, washed with brine, dried over Na₂SO₄, concentrated, andpurified on silica gel (ethyl acetate (EA)/petroleum ether (PE) 40%-70%)to give the title compound (25.0 mg, 57%) as a white solid. MS (ESI) m/z467.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.42 (s, 1H), 7.23 (s, 1H),7.00-6.98 (m, 2H), 6.74 (d, J=8.0 Hz, 1H), 5.76-5.73 (m, 1H), 4.52-4.45(m, 1H), 4.04-3.99 (m, 2H), 3.77 (s, 3H), 3.70-3.66 (m, 1H), 2.80 (s,3H), 2.21 (s, 3H), 1.40-1.36 (m, 3H).

Example 2: Compound 2:(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)pivalamide

To a solution of (S)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1-nitro-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione (400 mg, 0.88 mmol)in THF (10 mL) was added Pd/C (200 mg). The mixture stirred at RT underhydrogen overnight, then filtered, concentrated, and purified on silicagel to give(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione (281 mg, 75%) as a yellow solid.

To a solution of(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(100 mg, 0.236 mmol) in pyridine (5 mL) was added pivaloyl chloride (56mg, 0.47 mmol) at 0° C. The mixture was stirred at RT for 4 h, dilutedwith water then extracted with EA. The combined organic layers werewashed with HCl (1N), dried over Na₂SO₄, filtered, concentrated, andpurified on silica gel eluting with EA/PE from 40% to 70% to give thetitle compound (21.0 mg, 17.5%) as a white solid. MS (ESI) m/z=509.1[M+H]⁺. ¹H NMR (DMSO-d6, 400 MHz) δ 11.52 (s, 1H), 7.81 (s, 1H), 7.04(s, 1H), 6.93 (s, 2H), 5.74 (d, J=8.8 Hz, 1H), 4.40-4.33 (m, 1H), 4.09(d, J=12.0 Hz, 1H), 4.01 (d, J=6.8 Hz, 2H), 3.73 (s, 3H), 3.02 (s, 3H),1.36-1.21 (m, 12H).

Example 3: Compound 3:(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2-methoxyacetamide

To a cooled (0° C.) solution of(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(40 mg, 0.094 mmol) in pyridine (3 mL) was added 2-methoxyacetylchloride (0.1 mL in 1 mL DCM). The mixture was stirred at 0° C. for 0.5h. HCl (2M, 3 mL) was added and the organic layer was washed with brine,dried over Na₂SO₄, concentrated and purified on silica gel eluting withEA/PE from 40% to 70% to give the title compound (15 mg, 32%) as a whitesolid. MS (ESI) m/z 497.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.77 (s,1H), 7.36 (s, 1H), 7.10-7.08 (m, 2H), 6.83 (d, J=8.8 Hz, 1H), 5.81 (dd,J=4.8 Hz, 10.4 Hz, 1H), 4.56-4.50 (m, 1H), 4.14-4.08 (m, 4H), 3.85 (s,3H), 3.73 (dd, J=3.6 Hz, 14.4 Hz, 1H), 3.55 (s, 3H), 2.85 (s, 3H), 1.47(t, J=6.8 Hz, 3H).

Example 4: Compound 4:(S)—N-(cyclopropanecarbonyl)-N-(5-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)cyclopropanecarboxamide

To a solution of(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(200 mg, 0.472 mmol) in pyridine (5 mL) was added cyclopropanecarbonylchloride (171 mg, 1.416 mmol) at 0° C., and the mixture was stirred atRT overnight. The mixture was concentrated, diluted with water andextracted with EA. The combined organic layers were washed with HCl (1N)and dried over Na₂SO₄, filtered, concentrated, and purified by prep-TLC(PE/EA, 1:1) to give the title compound (60.7 mg, 61.4%) as a yellowsolid. MS (ESI) m/z=578.2 [M+H₂O]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 7.94 (s,1H), 7.05 (s, 1H), 6.96-6.90 (m, 2H), 5.70 (dd, J=9.6, 4.4 Hz, 1H),4.33-4.26 (m, 1H), 4.14-4.08 (m, 1H), 4.04-3.98 (m, 2H), 3.74 (s, 3H),2.99 (s, 3H), 2.20-2.17 (m, 1H), 2.06-2.03 (m, 1H), 1.32 (t, J=7.2 Hz,3H), 1.23-1.20 (m, 2H), 1.09-1.04 (m, 4H), 0.98 (s, 2H).

Example 5: Compound 5:N-(5-((S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-3,3,3-trifluoro-2-methylpropanamide

To a solution of 3,3,3-trifluoro-2-methylpropanoic acid (34 mg, 0.24mmol) in DMF (3 mL) was added 1-hydroxybenzotriazole (HOBt) (48 mg,0.354 mmol) and3-(ethyliminomethylideneamino)-N,N-dimethylpropan-1-amine hydrochloride(EDCI) (68 mg, 0.35 mmol), followed by DIEA (91 mg, 0.71 mmol).(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(100 mg, 0.236 mmol) was added and the solution was stirred at RT for 16h, concentrated and purified on silica gel eluting with EA/PE from 40%to 70% to give the title compound (14.5 mg, 11%) as a white solid. MS(ESI) m/z 547.1 [M−H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 7.86(s, 1H), 7.04 (s, 1H), 6.93 (s, 2H), 5.71 ((dd, J=4.0 Hz, 10.0 Hz, 1H),4.35-4.28 (m, 1H), 4.13-4.09 (m, 2H), 4.02-3.97 (m, 2H), 3.73 (s, 3H),3.01 (s, 3H), 1.37-1.30 (m, 6H).

Example 6: Compound 6:S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2-ethylbutanamide

To a cooled (0 C) solution of(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(100 mg, 0.236 mmol) in pyridine (3 mL) was added 2-ethylbutanoylchloride (0.15 mL in 1 mL DCM). After the mixture was stirred at 0 C for0.5 h, HCl (2M, 3 mL) was added. The organic layer was washed withbrine, dried over Na₂SO₄, concentrated, and purified on silica geleluting with EA/PE from 40% to 70% to give the title compound (25.3 mg,20%) as a white solid. MS (ESI) m/z 523.2 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d6) δ 11.75 (s, 1H), 7.78 (s, 1H), 7.04 (s, 1H), 6.93 (s, 2H), 5.71((dd, J=4.4 Hz, 10.4 Hz, 1H), 4.36-4.29 (m, 1H), 4.11 ((dd, J=4.4 Hz,14.8 Hz, 1H), 4.02-3.97 (m, 2H), 3.73 (s, 3H), 3.01 (s, 3H), 2.78-2.74(m, 1H), 1.59-1.43 (m, 4H), 1.34-1.30 (m, 3H), 0.83-0.80 (m, 6H).

Example 7: Compound 7:(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2,2,2-trifluoroacetamide

A solution of thiophene-3,4-dicarboxylic acid (25.0 g, 145 mmol) inacetic anhydride (250 mL) was heated to 110° C. for 16 h. The mixturewas then concentrated to give thieno[3,4-c]furan-1,3-dione (22.0 gcrude) as a yellow solid and used for the next step without furtherpurification.

Thieno[3,4-c]furan-1,3-dione (22.0 g, 143 mmol) was added to nitric acid(95%, 90 mL) at 0-5° C. over 1 h. The mixture was warmed to RT for 1 hthen poured into ice water and extracted with EA. The combined organiclayers were dried over Na₂SO₄, filtered and concentrated to give2-nitrothiophene-3,4-dicarboxylic acid (20.8 g, 66%) as a yellow solidand used for the next step without further purification.

A solution of 2-nitrothiophene-3,4-dicarboxylic acid (6.0 g, 27.6 mmol)in Ac₂O (60 mL) was heated to 140° C. for 3 h. The mixture wasconcentrated to give 4-nitrothieno[3,4-c]furan-1,3-dione (5.5 g) as ayellow solid and used for the next step without further purification.

A mixture of 4-nitrothieno[3,4-c]furan-1,3-dione (5.5 g, 27.64 mmol),and (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (7.54g, 27.64 mmol) in THF (250 mL) was stirred at RT for 16 h. Then1,1′-carbonyldiimidazol (CDI) (5.37 g, 33.1 mmol) was added and thereaction was heated to reflux for 3 h. The mixture was concentrated andpurified on silica gel eluting with EA/PE from 30% to 50% to give(S)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1-nitro-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(10.0 g, 79%) as a yellow solid.

A mixture of (S)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-1-nitro-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione (1.0 g, 2.2 mmol),NH₄Cl (706 mg, 13.2 mmol) and iron powder (740 mg, 13.2 mmol) inTHF/water (50 mL/10 mL) was heated to reflux for 1 h. The reaction wasfiltered, concentrated, and to purified on silica gel eluting with EA/PEfrom 40% to 70% to give(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione (300 mg, 32%) as a yellow solid. MS (ESI) m/z424.9 [M+H]⁺.

To a solution of(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(150 mg, 0.354 mmol) in ACN (3 mL) was added pyridine (1 mL). Themixture was cooled to 0° C., then trifluoroacetic anhydride (0.2 mL in 1mL ACN) was added at 0° C. for 0.5 h. HCl (2M, 3 mL) was added. Theorganic layer was washed with brine, dried over Na₂SO₄, concentrated andpurified on silica gel eluting with EA/PE from 40% to 70% to give thetitle compound (30 mg, 16%) as a white solid. MS (ESI) m/z 538.1[M+H₂O]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.09 (s, 1H), 6.98(s, 2H), 5.76-5.73 (m, 1H), 4.43-4.36 (m, 1H), 4.15-4.10 (m, 1H),4.07-4.03 (m, 2H), 3.78 (s, 3H), 3.06 (s, 3H), 1.39-1.36 (m, 3H).

Example 8: Compound 8:(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)cyclopropanecarboxamide

To a solution of cyclopropanecarboxylic acid (41 mg, 0.472 mmol) in DMF(5 mL) was added HOBt (95 mg, 0.71 mmol) and EDCI (136 mg, 0.71 mmol)followed by DIEA (183 mg, 1.5 mmol).(S)-1-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(200 mg, 0.472 mmol) was added and the solution was stirred at RT for 16h. The mixture was concentrated and purified on silica gel eluting withEA/PE from 40% to 70% to give the title compound (14 mg, 6%) as a yellowsolid. MS (ESI) m/z 493.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 12.01 (s,1H), 7.76 (s, 1H), 7.06 (s, 1H), 6.95 (s, 2H), 5.74-5.71 (m, 1H),4.35-4.31 (m, 1H), 4.14-4.09 (m, 1H), 4.04-3.99 (m, 2H), 3.74 (s, 3H),3.02 (s, 3H), 2.52-2.51 (m, 1H), 1.35-1.31 (m, 3H), 0.96-0.90 (m, 4H).

Example 9: Compound 9:(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)-2,2,2-trifluoroacetamide

To a solution of 4-bromothiophene-3-carboxylic acid (10.0 g, 48.35 mmol)in THF (100 mL) at RT was added hexamethylphosphoramide (1.75 g, 9.67mmol). The mixture was cooled to −70° C. and lithium diisopropylamide(53 mL, 106.5 mmol, 2M in THF) was added under N₂. The reaction wasstirred at this temperature for 1 h then CO₂ was bubbled for 30 min at−40° C. The reaction was warmed to RT and stirred for 15 min. Thereaction was quenched with water (100 mL) and adjusted to pH=10 with 10%NaOH (aq.). The mixture was extracted with EA and the aqueous layer wasadjusted to pH=3 with 1 N HCl, extracted with EA, dried over Na₂SO₄,filtered, concentrated, and washed with EA to give4-bromothiophene-2,3-dicarboxylic acid (5.6 g, 46.2%) as a red solid.

4-Bromothiophene-2,3-dicarboxylic acid (1.0 g, 4 mmol) was dissolved inacetic anhydride (10 mL), and the suspension was stirred at 135° C. for16 h. The solvent was removed and the residue was dried to give3-bromothieno[2,3-c]furan-4,6-dione (1.0 g, crude) as a brown solidwhich was used directly for the next step.

To a solution of 3-bromothieno[2,3-c]furan-4,6-dione (900 mg, 3.88 mmol)in THF (15 mL) at RT was added(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (1.06 g,3.88 mmol), and the mixture was stirred for 1 h. Then1,1′-carbonyldiimidazole (754.9 mg, 4.66 mol) was added and the mixturewas heated at 70° C. for 3 h. The reaction was concentrated and theresidue was purified on silica gel eluting with EA/PE from 10% to 50% togive(S)-3-bromo-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(5) (1.52 g, 80%) as a yellow solid. MS (ESI) m/z 504.9, 506.9 [M+H₂O]⁺.

To a suspension of(S)-3-bromo-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(500 mg, 1.03 mmol) in 1,4-dioxane/toluene (13 mL/13 mL) at RT was addeddiphenylmethanimine (223.4 mg, 1.23 mmol) and cesium carbonate (669.5mg, 2.06 mmol). The suspension was degassed and purged with nitrogentwice. Then tris(dibenzylideneacetone)dipalladium (Pd₂(dba)₃) (188.6 mg,0.206 mmol) and Xantphos (178.8 mg, 0.309 mmol) was added. Thesuspension was heated at 100° C. for 16 h. The mixture was cooled to RTand concentrated. The residue was purified on silica gel eluting withEA/PE from 10% to 50% to give (S)-3-((diphenylmethylene)amino)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(241 mg, 39.8%) as a yellow solid. MS (ESI) m/z 589.1 [M+H]⁺.

To a solution of(S)-3-((diphenylmethylene)amino)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(240 mg, 0.408 mmol) in MeOH (10 mL) at RT was added NH₂OH.HCl (113.4mg, 1.632 mmol) and NaOAc (167 mg, 2.04 mmol). The suspension wasstirred at RT for 5 h then concentrated. The residue was purified onsilica gel eluting with EA/PE from 10% to 50% to give(S)-3-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(83 mg, 48%) as a yellow gum. MS (ESI) m/z 424.9 [M+H]⁺.

To a solution of(S)-3-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(83 mg, 0.196 mmol) in DCM/pyridine (2 mL/2 mL) at 0° C. was added thesolution of trifluoroacetic anhydride (123 mg, 0.587 mmol) in DCM (0.5mL). The reaction was stirred at 0° C. for 10 min, quenched with water(1 mL) and extracted with DCM. The combined organic layers were washedwith 1N HCl, dried over Na₂SO₄, filtered, concentrated, and purified byprep-TLC (PE/EA, 1:1) to give the title compound (54.5 mg, 53.5%) as ayellow solid. MS (ESI) m/z 521.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ11.71 (s, 1H), 8.18 (s, 1H), 7.05 (s, 1H), 6.95 (s, 2H), 5.67 (dd,J=4.0, 10.4 Hz, 1H), 4.29 (dd, J=10.0, 14.0 Hz, 1H), 4.10 (dd, J=4.4,14.0 Hz, 1H), 4.01 (q, J=7.2 Hz, 2H), 3.74 (s, 3H), 3.00 (s, 3H), 1.32(t, J=6.8 Hz, 3H).

Example 10: Compound 10:(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)-2-methoxyacetamide

To a solution of(S)-3-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(73 mg, 0.172 mmol) in DCM/pyridine (2 mL/2 mL) at 0° C. was added thesolution of 2-methoxyacetyl chloride (37 mg, 0.344 mmol) in DCM (0.5mL). The reaction was stirred at 0° C. for 10 min and quenched withwater (1 mL) then extracted with DCM. The combined organic layers werewashed with 1 N HCl, dried over Na₂SO₄, filtered, concentrated, andpurified by prep-TLC (PE/EA, 1:1) to give the title compound (30.3 mg,35.6%) as a light yellow solid. MS (ESI) m/z 497.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d6) δ 9.55 (s, 1H), 8.31 (s, 1H), 7.04 (d, J=1.6 Hz, 1H),6.98-6.92 (m, 2H), 5.67 (dd, J=4.0, 10.4 Hz, 1H), 4.28 (dd, J=11.2, 14.4Hz, 1H), 4.10 (dd, J=4.4, 14.0 Hz, 1H), 4.09 (s, 2H), 4.01 (q, J=6.8 Hz,2H), 3.74 (s, 3H), 3.41 (s, 3H), 3.01 (s, 3H), 1.32 (t, J=6.8 Hz, 3H).

Example 11: Compound 11:(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)cyclopropanecarboxamide

To a solution of cyclopropanecarboxylic acid (533 mg, 6.19 mmol) in DCM(5 mL) at 0° C. was added a solution of oxalyl chloride (1.17 g, 9.28mmol) in DCM (1 mL). The reaction was stirred at 20° C. for 3 h thenconcentrated to give cyclopropanecarbonyl chloride (500 mg, crude) as ayellow oil. To a solution of(S)-3-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(37 mg, 0.087 mmol) in DCM/pyridine (2 mL/2 mL) at 0° C. was added asolution of cyclopropanecarbonyl chloride (10.5 mg, 0.131 mmol) in DCM(0.5 mL). The reaction was stirred at 0° C. for 10 minutes, quenchedwith water (1 mL) and extracted with DCM. The combined organic layerswere washed with 1 N HCl, dried over Na₂SO₄, filtered, concentrated, andpurified by prep-TLC (PE/EA, 1:1.5) to give the title compound (46.9 mg,64%) as a light yellow solid. MS (ESI) m/z 493.1, 510.1 [M+H, M+H2O]⁺.¹H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.26 (s, 1H), 7.06 (s, 1H),6.99-6.924 (m, 2H), 5.71 (dd, J=4.0, 10.4 Hz, 1H), 4.30 (dd, J=11.2,14.4 Hz, 1H), 4.11 (dd, J=4.4, 14.4 Hz, 1H), 4.02 (q, J=6.8 Hz, 2H),3.75 (s, 3H), 3.03 (s, 3H), 2.09 (t, J=6.0 Hz, 1H), 1.33 (t, J=6.8 Hz,3H), 0.83 (d, J=6.4 Hz, 2H).

Example 12: Compound 12 (S) and Compound 18 (R):N-(5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide

To a solution of(S)-1-amino-5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(130 mg, 0.33 mmol) in ACN (3 mL) was added pyridine (0.1 mL). Themixture was cooled to 0° C. then acetyl chloride (0.1 mL in 1 mL ACN)was added dropwise, and the mixture was stirred at 0° C. for 0.5 h. HCl(2M, 3 mL) was added, and the organic layer was washed with brine, driedover Na₂SO₄, concentrated, and purified by prep-HPLC (ACN/H₂O, 5%-95%)to give Compound 12 (49 mg, 34%) as a white solid. MS (ESI) m/z 437.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.75 (s, 1H), 7.06(s, 1H), 6.89 (s, 2H), 6.02 (d, J=4.0, 2H), 5.69 (q, 1H), 4.31 (q, 1H),4.08 (q, 1H), 3.01 (s, 3H), 2.23 (s, 1H). Compound 18 was preparedanalogously to Compound 12. MS (ESI) m/z 454.0 [M+H₂O]⁺.

Example 13: Compound 13 (S) and Compound 19 (R):N-(5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)cyclopropanecarboxamide

To a solution of(S)-1-amino-5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(180 mg, 0.46 mmol) in ACN (3 mL) was added pyridine (0.1 mL). Themixture was cooled to 0° C., then cyclopropanecarbonyl chloride (0.3 mLin 1 mL ACN, which was prepared from cyclopropanecarboxylic acid withSOCl₂ reflux for 2H) was added drop wised, the mixture was stirred at 0°C. for 0.5 h. HCl (2M, 3 mL) was added, the organic layer was washedwith brine, dried over Na₂SO₄, concentrated and purified by prep-HPLC(ACN/H₂O=5%-95%) to give the title compound (48 mg, 23%) as a whitesolid. MS (ESI) m/z 463.8 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 11.98 (s,1H), 7.75 (s, 1H), 7.07 (s, 1H), 6.90 (s, 2H), 6.02 (d, J=4.0, 2H), 5.70(q, 1H), 4.31 (q, 1H), 4.08 (q, 1H), 3.01 (s, 3H), 2.31 (m, 1H), 0.92(m, 4H). Compound 19 was prepared analogously to Compound 13. MS (ESI)m/z 463.8 [M+H]⁺.

Example 14: Compound 14 (S) and Compound 20 (R):N-(5-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide

A solution of 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (10.0 g,60.97 mmol) in DMF (100 mL) was added dimethyl sulfone (11.0 g, 121.95mmol) and NaOH (3.7 g, 91.46 mmol). The mixture was heated to 50° C. for2 h, then concentrated and purified on silica gel eluting with EA/PEfrom 50% to 80% to give(E)-6-(2-(methylsulfonyl)vinyl)-2,3-dihydrobenzo[b][1,4]dioxine (5.3 g,36%) as a yellow solid. MS (ESI) m/z 241.2 [M+1]⁺.

A mixture of(E)-6-(2-(methylsulfonyl)vinyl)-2,3-dihydrobenzo[b][1,4]dioxine (5.3 g,22.08 mmol) and hydroxylamine (7.3 g, 221.2 mmol) in THF (50 mL) washeated to reflux overnight. The mixture was concentrated and purified onsilica gel eluting with EA/PE from 80% to 100% to giveN-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)ethyl)hydroxylamine(3.8 g, 62%) as a colorless oil. MS (ESI) m/z 275.1 [M+1]⁺.

A mixture ofN-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)ethyl)hydroxylamine(3.8 g, 13.90 mmol) and Pd/C (380 mg) in MeOH (30 mL) was stirred at RTunder hydrogen overnight. The mixture was filtered and the filtrate wasconcentrated to give crude1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)ethanamine.Chiral prep-HPLC afforded the two enantiomers: S isomer (peak 1, 320 mg)as a white solid and R isomer (peak 2, 350 mg) as a white solid. Sisomer MS (ESI) m/z 258.3 [M+1]⁺.

A mixture of 4-nitrothieno[3,4-c]furan-1,3-dione (199 mg, 1.0 mmol) and(S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)ethanamine(257 mg, 1.0 mmol) in THF (15 mL) was stirred at RT for 1 h.1,1′-Carbonyldiimidazol (195 mg, 1.2 mmol) was added and the mixture wasstirred at 80 C for 1 h. The mixture was diluted with EA (100 mL),washed with water (100 mL) and brine (50 mL), dried over Na₂SO₄,concentrated, and purified on silica gel eluting with EA/PE (1:1) togive(S)-5-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)ethyl)-1-nitro-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(7) (300 mg, 68%) as a yellow solid. MS (ESI)m/z 439.1 [M+1]⁺.

A mixture of(S)-5-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)ethyl)-1-nitro-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(150 mg, 0.34 mmol), ammonium chloride (91 mg, 1.7 mmol) and iron powder(96 mg, 1.7 mmol) in THF/water (10 mL/3 mL) was stirred at 80° C. for 1h. The reaction was diluted with EA (100 mL), washed with water (100 mL)and brine (50 mL), dried over Na₂SO₄, concentrated, and purified onsilica gel eluting with EA/PE (2:1) to give(S)-1-amino-5-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(21 mg, 15%) as a yellow solid. MS (ESI) m/z 409.1 [M+H]⁺.

To a solution of(S)-1-amino-5-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(21 mg, 0.05 mmol) in pyridine (4 mL) was added acetyl chloride (0.1 mL)at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction wasquenched with water (50 mL) and extracted with EA (50 mL). The organicphase was washed with 0.5 N HCl (20 mL) and brine (50 mL). The organicphase was dried over Na₂SO₄, concentrated, and purified by prep-HPLC(ACN/H₂O, 5%-95%) to give the title compound (10.5 mg, 47%) as a whitesolid. MS (ESI) m/z 451.0 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.27 (s,1H), 7.32 (s, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.97 (dd, J=2.0, 8.4 Hz, 1H),6.84 (d, J=8.4 Hz, 1H), 5.80 (dd, J=4.0, 10.4 Hz, 1H), 4.55 (dd, J=10.4,14.4 Hz, 1H), 4.23 (s, 4H), 3.70 (dd, J=4.0, 14.4 Hz, 1H), 2.90 (s, 3H),2.28 (s, 3H). Compound 20 was prepared analogously to Compound 14. MS(ESI) m/z 468.0 [M+H₂O]⁺.

Example 15: Compound 15:(S)—N-(5-(2-(N,N-dimethylsulfamoyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide

To a solution of N,N-dimethylmethanesulfonamide (23.9 g, 194.23 mmol) inN,N-dimethylacetamide (150 mL) was added KOH (6.54 g, 116.55 mmol) atRT. The mixture was stirred for 15 min at RT. Then3-ethoxy-4-methoxybenzaldehyde (14 g, 77.7 mmol) was added and themixture was stirred for 2 h at 60° C. The mixture was poured onto icewater (300 mL) and filtered, and purified on silica gel to afford(E)-2-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylethenesulfonamide (9.5 g,43%) a white solid. MS (ESI) m/z=286.1 [M+H]⁺.

To a solution of(E)-2-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylethenesulfonamide (7.3 g,25.56 mmol) in THF (70 mL) was added hydroxylamine (60 mL, 2.2 mol) atRT. The mixture was warmed to 60° C. and stirred for 16 h. The mixturewas poured onto ice water (50 mL) and stirred for 10 minutes thenextracted with EA. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and evaporated. The mixture wasconcentrated and purified on silica gel to afford2-(3-ethoxy-4-methoxyphenyl)-2-(hydroxyamino)-N,N-dimethylethanesulfonamide(4.5 g, 55%) a white solid. MS (ESI) m/z=319.0 [M+H]⁺.

To a solution of2-(3-ethoxy-4-methoxyphenyl)-2-(hydroxyamino)-N,N-dimethylethanesulfonamide(4.5 g, 14.13 mmol) in MeOH (50 mL) at RT was added Pd/C (1 g). Themixture was stirred at RT overnight under hydrogen. The suspension wasfiltered through a pad of celite and the filtrate was concentrated. Theresidue was purified on silica gel to afford2-amino-2-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylethanesulfonamide (3.8g, 89%) a white solid. Chiral Prep-HPLC gave two enantiomers: S isomer(peak 1, 1.5 g) as a white solid and R isomer (peak 2, 1.4 g) as a whitesolid. S isomer MS (ESI) m/z=303.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ7.02 (s, 1H), 6.91-6.85 (m, 1H), 4.28-4.24 (m, 1H), 4.04-3.97 (m, 2H),3.72 (m, 3H), 3.29-3.21 (m, 1H), 3.15-3.09 (m, 1H), 2.74-2.69 (m, 6H),2.08 (m, 2H), 1.34-1.30 (m, 3H).

A mixture of 4-nitrothieno[3,4-c]furan-1,3-dione (199 mg, 1.0 mmol) and(S)-2-amino-2-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylethanesulfonamide(302 mg, 1.0 mmol) in THF (10 mL) was stirred at RT for 1 h.1,1′-Carbonyldiimidazol (211 mg, 1.3 mmol) was added and the mixture wasstirred at 80° C. for 1 h. The reaction was diluted with EA (100 mL),washed with water (100 mL) and brine (50 mL), dried, concentrated, andpurified on silica gel (PE/EA, 2:3) to give(S)-2-(3-ethoxy-4-methoxyphenyl)-N,N-dimethyl-2-(1-nitro-4,6-dioxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)ethanesulfonamide(415 mg, 86%) as a yellow solid. MS (ESI) m/z 484.1 [M+1]⁺.

A mixture of(S)-2-(3-ethoxy-4-methoxyphenyl)-N,N-dimethyl-2-(1-nitro-4,6-dioxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)ethanesulfonamide(410 mg, 0.85 mmol), ammonium chloride (228 mg, 4.25 mmol) and ironpowder (238 mg, 4.25 mmol) in THF/water (10 mL/3 mL) was heated toreflux for 1 h. The reaction was diluted with EA (100 mL), washed withwater (100 mL) and brine (50 mL), dried, concentrated, and purified onsilica gel (PE/EA, 2:3) to give(S)-2-(1-amino-4,6-dioxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-2-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylethanesulfonamide(110 mg, 29%) as a yellow semi-solid. MS (ESI) m/z 439.1[M+H]⁺.

To a solution of(S)-2-(1-amino-4,6-dioxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-2-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylethanesulfonamide(110 mg, 0.25 mmol) in pyridine (6 mL) was added acetyl chloride (198mg, 2.5 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h. Thereaction was quenched with water (50 mL), extracted with EA (50 mL), theorganic phase was washed with 0.5 N HCl (20 mL) and brine (50 mL). Theorganic phase was dried over Na₂SO₄, concentrated, and purified withprep-TLC (PE/EA, 1:1) to give the title compound (67 mg, 54%) as a whitesolid. MS (ESI) m/z 496.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s,1H), 7.32 (s, 1H), 7.08-7.05 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 5.74 (dd,J=3.2, 11.2 Hz, 1H), 4.56 (dd, J=11.2, 14.4 Hz, 1H), 4.10 (q, J=6.8 Hz,2H), 3.85 (s, 3H), 3.42 (dd, J=3.2, 14.4 Hz, 1H), 2.84 (s, 6H), 2.29 (s,3H), 1.47 (t, J=6.8 Hz, 3H).

Example 16: Compound 16 (S) and Compound 17 (R):N-(5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)-2,2,2-trifluoroacetamide

To a solution of 3, 4-dihydroxybenzaldehyde (50.0 g, 37.5 mmol) in DMF(500 mL) was added DCM (50.0 g, 588.9 mmol) and K₂CO₃ (7.76 g, 52.25mmol). The mixture was heated to 120° C. for 2 h then concentrated andpurified on silica gel eluting with EA/PE from 50% to 70% to givebenzo[d][1,3]dioxole-5-carbaldehyde (49 g, 90%) as a black solid. MS(ESI) m/z 151.1 [M+1]⁺.

A solution of benzo[d][1,3]dioxole-5-carbaldehyde (38.0 g, 253.33 mmol)in DMF (400 mL) was added dimethyl sulfone (59.7 g, 633.33 mmol) andNaOH (15.2 g, 380 mmol). The mixture was heated to 50° C. for 2 h thenconcentrated and purified on silica gel eluting with EA/PE from 50% to80% to give (E)-5-(2-(methylsulfonyl)vinyl)benzo[d][1,3]dioxole (24.0 g,44.1%) as a yellow solid. MS (ESI) m/z 227.3 [M+1]⁺.

A mixture of (E)-5-(2-(methylsulfonyl)vinyl)benzo[d][1,3]dioxole (24.0g, 106.05 mmol) and hydroxylamine (29.1 g, 221.2 mmol) in THF (200 mL)was heated to reflux for overnight. The mixture was concentrated andpurified on silica gel (PE/EA=80%-100%) to giveN-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)hydroxylamine(12.0 g, 43.7%) as a colorless oil. MS (ESI) m/z 260.3 [M+1]⁺.

A mixture of N-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)hydroxylamine (12.0 g, 13.78 mmol) and Pd/C (1.2 g) in MeOH (30 mL) wasstirred at RT under H₂ overnight. The mixture was filtered and thefiltrate was concentrated and purified on silica gel eluting with EA/PEfrom 80% to 100% to give1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethanamine (5.4 g, 48%)as a white solid. Chiral prep-HPLC afforded the two enantiomers as whitesolids: S isomer (peak 1, 2.53 g, 93.7%); R isomer (peak 2, 2.5 g,92.6%). S isomer MS (ESI) m/z 243.3 [M+1]⁺.

A mixture of 4-nitrothieno[3,4-c]furan-1,3-dione (357 mg, 1.79 mmol),and (S)-1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethanamine (420mg, 1.79 mmol) in THF (15 mL) was stirred at RT for 1 h then1,1′-carbonyldiimidazole (348 mg, 2.15 mmol) was added and the reactionwas heated to reflux for another 1 h. The mixture was concentrated andthe residue was purified on silica gel eluting with EA/PE from 30% to50% to give(S)-5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-1-nitro-4H-thieno-[3,4-c]pyrrole-4,6(5H)-dione(630 mg, 83%) as a yellow solid. MS (ESI) m/z 426.1 [M+1]⁺.

A mixture of (S)-5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-1-nitro-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione (500 mg, 1.18mmol), ammonium chloride (375 mg, 7.08 mmol) and iron powder (528 mg,5.34 mmol) in THF/water (5 mL/2 mL) was heated to reflux for 1 h. Thereaction was filtered, concentrated, and purified on silica gel elutingwith EA/PE from 40% to 70% to give(S)-1-amino-5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(160 mg, 35%) as a yellow solid. MS (ESI) m/z 394.1 [M+H]⁺.

To a solution of(S)-1-amino-5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4H-thieno[3,4-c]pyrrole-4,6(5H)-dione(160 mg, 0.41 mmol) in ACN (3 mL) was added pyridine (0.1 mL). Themixture was cooled to 0° C., then trifluoroacetic anhydride (0.1 mL in 1mL ACN) was added dropwise. The mixture was stirred at 0° C. for 0.5 hthen HCl (2M, 3 mL) was added. The organic layer was washed with brine,dried over Na₂SO₄, concentrated, and purified by prep-HPLC(ACN/H₂O=5%-95%) to give Compound 16 (49 mg, 24%) as a white solid. MS(ESI) m/z 508.1 [M+H₂O]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.06(s, 1H), 6.89 (s, 2H), 6.01 (d, J=4.0, 2H), 5.70 (q, 1H), 4.31 (q, 1H),4.08 (q, 1H), 3.01 (s, 3H). Compound 17 was prepared analogously toCompound 16. MS (ESI) m/z 508.0 [M+H₂O]⁺.

Example 17: Compound 21 (S) and Compound 22 (R):N-(5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)-2,2,2-trifluoroacetamide

To a solution of 3-bromothieno[2,3-c]furan-4,6-dione (317.6 mg, 1.37mmol) in THF (10 mL) at RT was added1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethanamine (333 mg, 1.37mmol). The mixture was stirred for 1 h then 1,1′-carbonyldiimidazol(332.9 mg, 2.06 mol) was added and the mixture was heated at 70° C. for1 h. The reaction was cooled and concentrated. The residue was purifiedon silica gel eluting with EA/PE from 10% to 50% to give5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-3-bromo-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(502 mg, 77.1%) as a light yellow solid. MS (ESI) m/z 474.8, 476.8.[M+H₂O]⁺.

To a suspension of5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-3-bromo-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(316 mg, 0.693 mmol) in 1,4-dioxane/toluene (15 mL/15 mL) at RT wasadded diphenylmethanimine (188 mg, 1.04 mmol) and CsCO₃ (450 mg, 1.38mmol). The suspension was degassed and purged with nitrogen twice.Tris(dibenzylideneacetone)dipalladium Pd₂(dba)₃ (253 mg, 0.277 mmol) andXantphos (240 mg, 0.416 mmol) was added. The suspension was heated at100° C. for 16 h. The reaction was cooled and concentrated. The residuewas purified on silica gel eluting with EA/PE from 10% to 50% to give5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-3-((diphenylmethylene)amino)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(241 mg, 39.8%) as a yellow gum. MS (ESI) m/z 559.0 [M+H]⁺.

To a solution of5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-3-((diphenylmethylene)amino)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione (163 mg, 0.293 mmol) inMeOH/DCM (8 mL/2 mL) at RT was added hydroxylamine hydrochloride (81 mg,1.632 mmol) and NaOAc (120 mg, 1.465 mmol). The suspension was stirredat RT for 3 h, concentrated, and purified on silica gel eluting withEA/PE from 10% to 50% to give3-amino-5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(83 mg, 48%) as a yellow solid. MS (ESI) m/z 394.9 [M+H]⁺.

To a solution of3-amino-5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione (32 mg, 0.081 mmol) inDCM/pyridine (2 mL/2 mL) at 0° C. was added a solution oftrifluoroacetic anhydride (86 mg, 0.405 mmol) in DCM (0.5 mL). Thereaction was stirred at 0° C. for 10 min, quenched with water (1 mL),and extracted with DCM. The combined organic layers were washed with 1NHCl, dried over Na₂SO₄, filtered, concentrated, and purified by prep-TLC(PE/EA, 1:1) to give the title compound (26.1 mg, 65.7%) as a lightyellow solid. Chiral prep-HPLC afforded the two enantiomers. (S)enantiomer (21): MS (ESI) m/z 508.0 [M+H₂O]⁺; ¹H NMR (400 MHz, DMSO-d6)δ 11.71 (s, 1H), 8.18 (s, 1H), 7.08 (s, 1H), 6.91 (s, 2H), 6.02 (dd,J=1.2, 3.6 Hz, 2H), 5.67 (dd, J=4.4, 10.0 Hz, 1H), 4.27 (dd, J=10.8,14.4 Hz, 1H), 4.09 (dd, J=4.8, 14.4 Hz, 1H), 3.01 (s, 3H). (R)enantiomer (22): MS (ESI) m/z 508.0 [M+H₂O]⁺.

Example 18: Compound 23 (S) and Compound 24 (R):N-(5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)acetamide

To a solution of3-amino-5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(49 mg, 0.125 mmol) in DCM/pyridine (2 mL/2 mL) at 0° C. was added asolution of acetyl chloride (49 mg, 0.623 mmol) in DCM (0.5 mL). Thereaction was stirred at 0° C. for 10 min then quenched with water (1 mL)and extracted with DCM. The combined organic layers were washed with 1 NHCl, dried over Na₂SO₄, filtered, concentrated, and purified by prep-TLC(PE/EA=1/1) to give the title compound (21.4 mg, 39.5%) as a lightyellow solid. Chiral prep-HPLC afforded the two enantiomers. (S)enantiomer (23): MS (ESI) m/z 437.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ10.07 (s, 1H), 8.28 (s, 1H), 7.08 (s, 1H), 6.91 (s, 2H), 6.02 (d, J=2.4Hz, 2H), 5.68 (dd, J=4.4, 10.4 Hz, 1H), 4.27 (dd, J=10.8, 14.4 Hz, 1H),4.08 (dd, J=4.4, 14.4 Hz, 1H), 3.02 (s, 3H), 2.11 (s, 3H). (R)enantiomer (24): MS (ESI) m/z 454.0 [M+H₂O]⁺.

Example 19: Compound 25 (S) and Compound 26 (R):N-(5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)-2-methoxyacetamide

To a solution of3-amino-5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrole-4,6(5H)-dione(32 mg, 0.081 mmol) in DCM/pyridine (2 mL/2 mL) at 0° C. was added asolution of 2-methoxyacetyl chloride (44 mg, 0.407 mmol) in DCM (0.5mL). The reaction was stirred at 0° C. for 10 min then quenched with H₂O(1 mL) and extracted with DCM. The combined organic layers were washedwith 1 N HCl, dried over Na₂SO₄, filtered, concentrated, and purified byprep-TLC (PE/EA, 1:1) to give the title compound (31.4 mg, 82.8%) as ayellow solid. Chiral prep-HPLC afforded the two enantiomers. (S)enantiomer (25): MS (ESI) m/z 467.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ9.54 (s, 1H), 8.31 (s, 1H), 7.08 (s, 1H), 6.91 (s, 2H), 6.02 (d, J=2.0Hz, 2H), 5.67 (dd, J=4.0, 10.0 Hz, 1H), 4.09 (dd, J=4.8, 9.6 Hz, 1H),4.08 (s, 2H), 3.42 (s, 3H), 3.02 (s, 3H). (R) enantiomer (26): MS (ESI)m/z 484.1 [M+H₂O]⁺.

Example 20: Compound 27 (S) and Compound 28 (R):N-(5-(1-(benzo[d][1,3]dioxol-5-yl)-2-(N,N-dimethylsulfamoyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)acetamide

A solution of benzo[d][1,3]dioxole-5-carbaldehyde (8.0 g, 53.33 mmol) inDMF (100 mL) was added N,N-dimethylmethanesulfonamide (16.5 g, 133.33mmol) and NaOH (3.2 g, 80 mmol). The mixture was heated at 50° C. for 2h, concentrated, and purified on silica gel (PE/EA, 50%-80%) to give(E)-2-(benzo[d][1,3] dioxol-5-yl)-N,N-dimethylethenesulfonamide (6.2 g,45.5%) as a yellow solid. MS (ESI) m/z 256.3 [M+1]⁺.

A mixture of (E)-2-(benzo[d][1,3]dioxol-5-yl)-N,N-dimethylethenesulfonamide (6.2 g, 24.29 mmol) and NH₂OH (7.3 g, 221.2 mmol) in THF (50mL) was heated to reflux overnight. The mixture was concentrated andpurified on silica gel (PE/EA, 80%-100%) to give2-(benzo[d][1,3]dioxol-5-yl)-2-(hydroxyamino)-N,N-dimethylethanesulfonamide (3.6 g, 51.4%) as a colorless oil. MS (ESI) m/z 289.3[M+1]⁺.

A mixture of2-(benzo[d][1,3]dioxol-5-yl)-2-(hydroxyamino)-N,N-dimethylethanesulfonamide(3.6 g, 13.78 mmol) and Pd/C (360 mg) in MeOH (30 mL) was stirred at RTunder H₂ overnight. The mixture was filtered, concentrated, and purifiedon silica gel (PE/EA, 80%-100%) to give2-amino-2-(benzo[d][1,3]dioxol-5-yl)-N,N-dimethylethanesulfonamide (3 g,89%) as a white solid. MS (ESI) m/z 273.3 [M+1]⁺.

A mixture of 2-amino-2-(benzo[d][1,3]dioxol-5-yl)-N,N-dimethylethanesulfonamide (3 g, 11.02 mmol) and di-tert-butyl dicarbonate (3.6 g,16.51 mmol) in MeOH (30 mL) was stirred at RT overnight. The mixture wasconcentrated and purified on silica gel (PE/EA, 80%-100%) to givetert-butyl(1-(benzo[d][1,3]dioxol-5-yl)-2-(N,N-dimethylsulfamoyl)ethyl)carbamate (2.8 g, 68.3%) as a colorless oil. Chiralprep-HPLC afforded the two enantiomers as white solids: S isomer (peak1, 1.33 g, 95%); R isomer (peak 2, 1.3 g, 92.9%). S isomer MS (ESI) m/z373.4 [M+1]⁺.

A mixture of 4-nitrothieno[3,4-c]furan-1,3-dione (630 mg, 2.32 mmol) and(S)-2-amino-2-(benzo[d][1,3]dioxol-5-yl)-N,N-dimethylethanesulfonamide(390 mg, 1.96 mmol) in THF (10 mL) was stirred at RT for 1 h then1,1′-carbonyldiimidazol (381 mg, 2.35 mmol) was added. The reaction washeated to reflux for another 1 h then concentrated and purified onsilica gel (PE/EA, 30%-50%) to give(S)-2-(benzo[d][1,3]dioxol-5-yl)-N,N-dimethyl-2-(1-nitro-4,6-dioxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)ethanesulfonamide(420 mg, 47%) as a yellow solid. MS (ESI) m/z 453.9 [M+1]⁺.

A mixture of(S)-2-(benzo[d][1,3]dioxol-5-yl)-N,N-dimethyl-2-(1-nitro-4,6-dioxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)ethanesulfonamide(440 mg, 0.97 mmol), ammonium chloride (309 mg, 5.83 mmol) and ironpowder (326 mg, 5.83 mmol) in THF/water (5 mL/2 mL) was heated to refluxfor 1 h. The mixture was filtered, concentrated, purified on silica gel(PE/EA, 40%-70%) to give(S)-2-(1-amino-4,6-dioxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-2-(benzo[d][1,3]dioxol-5-yl)-N,N-dimethylethanesulfonamide(148 mg, 34%) as a yellow solid. MS (ESI) m/z 453.1[M+H]⁺.

To a solution of(S)-2-(1-amino-4,6-dioxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-2-(benzo[d][1,3]dioxol-5-yl)-N,N-dimethylethanesulfonamide(148 mg, 0.33 mmol) in DCM (3 mL) was added pyridine (0.1 mL). Themixture was cooled to 0° C. then acetyl chloride (0.1 mL in 1 mL ACN)was added dropwise. The mixture was stirred at 0° C. for 0.5 h. HCl (2M,3 mL) was added then the organic layer was washed with brine, dried overNa₂SO₄, concentrated and purified by prep-HPLC (ACN/H₂O, 5%-95%) to giveCompound 27 (65 mg, 43%) as a white solid. MS (ESI) m/z 466.0 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.76 (s, 1H), 7.09 (s, 1H), 6.90(s, 2H), 6.02 (d, J=4.0, 2H), 5.62 (q, 1H), 4.30-4.31 (m, 1H), 3.45-3.48(m, 1H), 2.77 (s, 6H), 2.24 (s, 1H). Compound 28 was preparedanalogously to Compound 27. MS (ESI) m/z 483.1 [M+H₂O]⁺.

Example 21: Compound 29:(R)—N-(5-(2-(N,N-dimethylsulfamoyl)-1-(3-ethoxy-4-methoxyphenyl)ethyl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-yl)acetamide

A mixture of(R)-2-(3-ethoxy-4-methoxyphenyl)-N,N-dimethyl-2-(1-nitro-4,6-dioxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)ethanesulfonamide(410 mg, 0.85 mmol), ammonium chloride (228 mg, 4.25 mmol) and ironpowder (238 mg, 4.25 mmol) in THF/water (10 mL/3 mL) was heated toreflux for 1 h. The reaction was diluted with EA (100 mL), washed withwater (100 mL) and brine (50 mL), dried over Na₂SO₄, concentrated, andpurified on silica gel (PE/EA, 2:3) to give(R)-2-(1-amino-4,6-dioxo-4H-thieno-[3,4-c]pyrrol-5(6H)-yl)-2-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylethanesulfonamide(110 mg, 29%) as a yellow semi-solid. MS (ESI) m/z 439.1 [M+H]⁺.

To a solution of(R)-2-(1-amino-4,6-dioxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)-2-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylethanesulfonamide(110 mg, 0.25 mmol) in pyridine (6 mL) was added acetyl chloride (198mg, 2.5 mmol) at 0° C., and stirred at 0° C. for 2 h. The reaction wasquenched with water (50 mL), extracted with EA (50 mL), and the organicphase was washed with 0.5N HCl (20 mL) and brine (50 mL). The organicphase was dried over Na₂SO₄, concentrated, and purified with prep-TLC(PE/EA, 1:1) to give the title compound (67 mg, 54%) as a white solid.MS (ESI) m/z 496.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 9.10 (s, 1H), 7.32(s, 1H), 7.08-7.05 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 5.74 (dd, J=3.2,11.2 Hz, 1H), 4.56 (dd, J=11.2, 14.4 Hz, 1H), 4.10 (q, J=6.8 Hz, 2H),3.85 (s, 3H), 3.42 (dd, J=3.2, 14.4 Hz, 1H), 2.84 (s, 6H), 2.29 (s, 3H),1.47 (t, J=6.8 Hz, 3H).

Example 22: Compound 30:(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)-2,2,2-trifluoroacetamide

To a stirred solution of methyl4-bromo-3-(bromomethyl)thiophene-2-carboxylate (628 mg, 2 mmol) and(S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine (819 mg,3.0 mmol) in ACN (20 mL) was added CsCO₃ (358 mg, 1.1 mmol). The mixturewas stirred at RT overnight then concentrated and purified on silica gel(PE/EA, 1:1) to give(S)-methyl-4-bromo-3-(((1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)amino)methyl)thiophene-2-carboxylate(905 mg, 90%) as yellow solid. MS (ESI) m/z 505.9 [M+H]⁺.

To a stirred solution of(S)-methyl4-bromo-3-(((1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)amino)methyl)thiophene-2-carboxylate(740 mg, 1.46 mmol) in THF (8 mL) and MeOH (8 mL) was added a solutionof lithium hydroxide (614 mg, 14.6 mmol) in water (8 mL). The mixturewas stirred at RT for 8 h then concentrated. The pH was adjusted to 4with 2 N HCl and the mixture extracted with DCM. The organic layer waswashed with brine, dried over Na₂SO₄, and evaporated to give(S)-4-bromo-3-(((1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)amino)methyl)thiophene-2-carboxylicacid (638 mg, 89%) as a yellow solid. MS (ESI) m/z 491.9 [M+H]⁺.

To a stirred solution of(S)-4-bromo-3-(((1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)amino)methyl)thiophene-2-carboxylicacid (628 mg, 1.27 mmol) in DCM (20 mL) was added oxalyl chloride (486mg, 3.8 mmol) dropwise then 2 drops of DMF was added. The mixture wasstirred at RT overnight then concentrated and purified on silica gel(DCM/MeOH, 10:1) to give(S)-3-bromo-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(398 mg, 66%) as a white solid. MS (ESI) m/z 473.9 [M+H]⁺.

To a stirred solution of(S)-3-bromo-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(364 mg, 0.77 mmol) and diphenylmethanimine (183 mg, 1.01 mmol) in1,4-dioxane (3.5 mL) and toluene (3.5 mL) was added CsCO₃ (511 mg, 1.56mmol) and tris(dibenzylideneacetone)dipalladium Pd₂(dba)₃ (73 mg, 0.08mmol) and Xantphos (110 mg, 0.21 mmol). The mixture was stirred at 108°C. (microwave) for 16 h. The mixture was diluted with water and EA. Theorganic layer was separated and washed with brine, dried by Na₂SO₄,filtered, evaporated, and purified by prep-TLC (Petroleum/EA, 1:1) togive(S)-3-((diphenylmethylene)amino)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(140 mg, 32%) as a yellow solid. MS (ESI) m/z 575.0 [M+H]⁺.

To a stirred solution of(S)-3-((diphenylmethylene)amino)-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(140 mg, 0.24 mmol) in EA (5 mL) was added a solution of HCl in EA (2.5mL). The mixture was stirred at RT for 20 min then concentrated andwashed with petroleum to give(S)-3-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(130 mg crude) as a yellow solid. MS (ESI) m/z 411.0 [M+H]⁺.

To a stirred solution of(S)-3-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(25 mg, 0.06 mmol) in DCM (1 mL) and pyridine (1 mL) was added asolution of trifluoroacetylchloride (38 mg, 0.18 mmol) in DCM (0.1 mL)at 0° C. The mixture was stirred at 0° C. for 30 min then quenched withwater and extracted with EA. The organic layer was washed with 1 N HClthen brine, and dried over Na₂SO₄, evaporated, and purified by prep-TLC(petroleum/EA, 1:1) to give the title compound (4 mg, 33%) as a whitesolid. MS (ESI) m/z 507.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s,1H), 6.99-6.92 (m, 3H), 5.82-5.78 (m, 1H), 4.54 (d, J=19.2 Hz, 1H),4.27-4.21 (m, 1H), 4.13-4.08 (m, 1H), 4.05-3.98 (m, 2H), 3.96-3.91 (m,1H), 3.74 (s, 3H), 3.01 (s, 3H), 1.74-1.72 (m, 1H), 1.31 (t, J=6.8 Hz,3H).

Example 23: Compound 31:(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)-2-methoxyacetamide

To a stirred solution of(S)-3-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(30 mg, 0.073 mmol) in DCM (1 mL) and pyridine (1 mL) was added asolution of 2-methoxyacetyl chloride (24 mg, 0.22 mmol) in DCM (0.1 mL)at 0° C. The mixture was stirred at 0° C. for 20 min then quenched withwater and extracted with EA. The organic layer was washed with 1 N HCl,then brine, and dried by Na₂SO₄, evaporated, and purified by prep-TLC(petroleum/EA, 1:2) to give the title compound (18 mg, 57%) as a whitesolid. MS (ESI) m/z 483.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 10.24 (s,1H), 7.77 (s, 1H), 6.98-6.91 (m, 3H), 5.81-5.77 (m, 1H), 4.49 (d, J=18.4Hz, 1H), 4.24-4.18 (m, 1H), 4.12-4.08 (m, 1H), 4.05-3.92 (m, 5H), 3.74(s, 3H), 3.35 (s, 3H), 3.00 (s, 3H), 1.31 (t, J=6.8 Hz, 3H).

Example 24: Compound 32:(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)cyclopropanecarboxamide

To a stirred solution of(S)-3-amino-5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-4H-thieno[2,3-c]pyrrol-6(5H)-one(40 mg, 0.098 mmol) in DCM (1 mL) and pyridine (1 mL) was added asolution of cyclopropanecarbonyl chloride (0.35 mmol) in DCM (0.2 mL) at0° C. The mixture was stirred at 0° C. for 30 min then quenched withwater and extracted with EA. The organic layer was washed with 1 N HClthen brine, and dried over Na₂SO₄, evaporated, and purified by prep-TLC(petroleum/EA, 1:2) to give(S)—N-(5-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)cyclopropanecarboxamide(7 mg, 22%) as a white solid. MS (ESI) m/z 479.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d6) δ 10.55 (s, 1H), 7.73 (s, 1H), 6.98-6.91 (m, 3H),5.79-5.76 (m, 1H), 4.74 (d, J=18.8 Hz, 1H), 4.21-4.14 (m, 1H), 4.06-3.93(m, 4H), 3.74 (s, 3H), 3.00 (s, 3H), 1.74-1.72 (m, 1H), 1.34-1.31 (m,3H), 0.85-0.78 (m, 4H).

Cell-Based TNFα Inhibition Assay

PBMCs induced with LPS (lipopolysaccharide): Frozen primary bloodmononuclear cells (PBMCs) are purchased from AllCells. Cells are quickthawed, washed once with Roswell Park Memorial Institute medium(RPMI)-1640/10% FBS/1% Penicillin/1% Streptomycin and plated in 96 wellplates at 200,000 cells per well. Cells are pretreated with DMSO only orthe indicated compounds for 1 hr and then induced with 100 ng/mL for18-24 hrs. The supernatant is analyzed for TNF-α using Meso Scale assayaccording to manufacturer's protocol. The negative control wells aretreated with DMSO. Compound activity is measured as a percentage of theDMSO control.

CHART 1 TNFα Inhibition % TNFα Inhibition % TNFα Inhibition Compound No.(0.1 μM) (1 μM) 1 B A 2 D A 3 B A 4 D B 5 C A 6 B A 7 D D 8 D A 9 D B 10D B 11 D C 12 D D 13 D D 14 D D 15 D D 16 D D 17 D D 18 D D 19 D D 20 DD 21 D D 22 C C 23 C B 24 D D 25 D C 26 D D 27 D D 28 D D 29 D D 30 D D31 D D 32 D C For TNFα inhibition assay: A = a single percent inhibitionvalue ≥60%; B = a single percent inhibition value <60% and >40%; C = asingle percent inhibition value ≤40% and >20%; and D = a single percentinhibition value ≤20%.

While the disclosure has been illustrated and described in detail in thedrawings and foregoing description, such illustration and descriptionare to be considered illustrative or exemplary and not restrictive. Thedisclosure is not limited to the disclosed embodiments. Variations tothe disclosed embodiments can be understood and effected by thoseskilled in the art in practicing the claimed disclosure, from a study ofthe drawings, the disclosure and the appended claims.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art, and are not to be limited to a special orcustomized meaning unless expressly so defined herein. It should benoted that the use of particular terminology when describing certainfeatures or aspects of the disclosure should not be taken to imply thatthe terminology is being re-defined herein to be restricted to includeany specific characteristics of the features or aspects of thedisclosure with which that terminology is associated.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

It will be further understood by those within the art that if a specificnumber of an introduced claim recitation is intended, such an intentwill be explicitly recited in the claim, and in the absence of suchrecitation no such intent is present.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term ‘about.’ Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it is apparent to those skilled in the art that certainchanges and modifications may be practiced. Therefore, the descriptionand examples should not be construed as limiting the scope of theinvention to the specific embodiments and examples described herein, butrather to also cover all modification and alternatives coming with thetrue scope and spirit of the invention.

What is claimed is:
 1. A compound of Formula (I), Formula (II), or a pharmaceutically acceptable salt of any of the foregoing,

wherein: Y is H, deuterium, halogen, or an optionally substituted C₁-C₆ alkyl; X and X₁ are each independently CH₂, C═O, SO, SO₂, or CH₂CO; R₁ is H, deuterium, hydroxy, halogen, nitro, cyano, optionally substituted C₁-C₆ alkoxy, —NH₂, —NHR_(1A), —NR_(1A)R_(1B), —NHC(O)R_(1C), —NR_(1A)C(O)R_(1C), —NHSO₂R_(1C), —NR_(1A)SO₂R_(1C), —N[C(O)R_(1A)][C(O)R_(1C)], an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl; R_(1A), R_(1B), and R_(1C) are independently selected from an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl; R₂ is hydroxy, —NH₂, —NHR_(1A), —NR_(1A)R_(1B), an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl; R₃, R₆, and R₇ are independently selected from a hydrogen, a deuterium, a halogen, an optionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆ alkoxy, an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, and an optionally substituted 5 to 10 membered heteroaryl; R₄ and R₅ are independently selected from an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, and an optionally substituted 5 to 10 membered heteroaryl; or R₄ and R₅, together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl; when R₂ is an optionally substituted C₁-C₄ alkyl or NH(C₁-C₆ alkyl), at least one of R₄ and R₅ is an optionally substituted cyclopropyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, an optionally substituted 5 to 10 membered heteroaryl, or R₄ and R₅, together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl; and R₈ is hydrogen or deuterium.
 2. The compound of Formula (I) or Formula (II) of claim 1, or a pharmaceutically acceptable salt of any of the foregoing,

wherein: Y is H, deuterium, halogen, or an optionally substituted C₁-C₆ alkyl; X and X₁ are each independently CH₂, C═O, SO, SO₂, or CH₂CO; R₁ is H, deuterium, hydroxy, halogen, nitro, cyano, optionally substituted C₁-C₆ alkoxy, —NH₂, —NHR_(1A), —NR_(1A)R_(1B), —NHC(O)R_(1C), —NR_(1A)C(O)R_(1C), —NHSO₂R_(1C), —NR_(1A)SO₂R_(1C), an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl; R_(1A), R_(1B), and R_(1C) are independently selected from an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl; R₂ is hydroxy, —NH₂, —NHR_(1A), —NR_(1A)R_(1B), an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl; R₃, R₆, and R₇ are independently selected from a hydrogen, a deuterium, a halogen, an optionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆ alkoxy, an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, and an optionally substituted 5 to 10 membered heteroaryl; R₄ and R₅ are independently selected from an optionally substituted C₁-C₆ alkyl, an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, and an optionally substituted 5 to 10 membered heteroaryl; or R₄ and R₅, together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl; when R₂ is an optionally substituted C₁-C₄ alkyl or NH(C₁-C₆ alkyl), at least one of R₄ and R₅ is an optionally substituted cyclopropyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, an optionally substituted 5 to 10 membered heteroaryl, or R₄ and R₅, together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl; wherein, when a C₁-C₆ alkyl, a C₁-C₆ alkoxy, a C₃-C₆ cycloalkyl, a C₆-C₁₀ aryl, a 3 to 10 membered heterocyclyl, or a 5 to 10 membered heteroaryl is substituted, the substituted substituents are independently selected from a deuterium, an oxo, a halogen, cyano, a nitro, an optionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆ alkoxy, an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted C₆-C₁₀ aryl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted 5 to 10 membered heteroaryl, —C(O)R_(A), —C(O)OR_(A), —C(O)NR_(B)R_(C), —OR_(A), —OC(O)R_(A), —OC(O)NR_(B)R_(C), —OS(O)R_(A), —OS(O)₂R_(A), —OS(O)NR_(B)R_(C), —OS(O)₂NR_(B)R_(C), —NR_(B)R_(C), —NR_(A)C(O)R_(A), —NR_(A)C(O)OR_(A), —NR_(A)C(O)NR_(B)R_(C), —NR_(A)S(O)R_(A), —NR_(A)S(O)₂R_(A), —NR_(A)S(O)NR_(B)R_(C), —NR_(A)S(O)₂NR_(B)R_(C), —SR_(A), —S(O)R_(A), —S(O)₂R_(A), —S(O)NR_(B)R_(C), and —S(O)₂NR_(B)R_(C); and each R_(A), R_(B), and R_(C) are independently selected from a hydrogen, a deuterium, an unsubstituted C₁-C₆ alkyl, an unsubstituted C₂-C₆ alkenyl, an unsubstituted C₃-C₆ cycloalkyl, an unsubstituted 3 to 10 membered heterocyclyl, an unsubstituted C₆-C₁₀ aryl, and an unsubstituted 5 to 10 membered heteroaryl; or R_(B) and R_(C), together with the nitrogen atom to which they are attached, form an optionally substituted 3 to 10 membered heterocyclyl.
 3. The compound of claim 1, wherein one of X and X₁ is CH₂ and the other is C═O.
 4. The compound of claim 1, wherein X is C═O and X₁ is CH₂.
 5. The compound of claim 1, wherein X and X₁ are each C═O.
 6. The compound of claim 1, wherein R₁ is —NHR_(1A), —NR_(1A)R_(1B), —NHC(O)R_(1C), —N[C(O)R_(1A)][C(O)R_(1C)], or —NR_(1A)C(O)R_(1C).
 7. The compound of claim 6, wherein R₁ is —NHC(O)R_(1C).
 8. The compound of claim 1, wherein R_(1A), R_(1B), and R_(1C) are independently an optionally substituted C₁-C₆ alkyl or an optionally substituted C₃-C₆ cycloalkyl.
 9. The compound of claim 1, wherein R_(1C) is an optionally substituted C₁-C₆ alkyl.
 10. The compound of claim 9, wherein R_(1C) is an unsubstituted C₁-C₆ alkyl.
 11. The compound of claim 1, wherein R₃, R₆, and R₇ are independently selected from a hydrogen, a halogen, and an optionally substituted C₁-C₆ alkyl.
 12. The compound of claim 11, wherein R₃, R₆, and R₇ are each hydrogen.
 13. The compound of claim 1, wherein R₂ is an optionally substituted C₁-C₆ alkyl and one of R₄ and R₅ is an optionally substituted C₁-C₆ alkyl and the other is an optionally substituted C₃-C₆ cycloalkyl or an optionally substituted 3 to 10 membered heterocyclyl.
 14. The compound of claim 1, wherein R₂ is an unsubstituted C₁-C₆ alkyl and one of R₄ and R₅ is an unsubstituted C₁-C₆ alkyl and the other is an optionally substituted C₃-C₆ cycloalkyl or an optionally substituted 3 to 10 membered heterocyclyl.
 15. The compound of claim 1, wherein R₂ is an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl, and R₄ and R₅ are independently an optionally substituted C₁-C₆ alkyl.
 16. The compound of claim 15, wherein R₂ is an optionally substituted C₃-C₆ cycloalkyl, an optionally substituted 3 to 10 membered heterocyclyl, an optionally substituted C₆-C₁₀ aryl, or an optionally substituted 5 to 10 membered heteroaryl, and R₄ and R₅ are independently unsubstituted C₁-C₆ alkyl.
 17. The compound of claim 1, wherein R₄ and R₅, together with the atoms to which they are attached, form an optionally substituted 5 or 6 membered heterocyclyl.
 18. The compound of claim 17, wherein R₄ and R₅, together with the atoms to which they are attached, form an unsubstituted 5 or 6 membered heterocyclyl.
 19. The compound of claim 18, wherein R₄ and R₅, together with the atoms to which they are attached, form an unsubstituted 5 membered heterocyclyl.
 20. The compound of claim 18, wherein R₄ and R₅, together with the atoms to which they are attached, form an unsubstituted 6 membered heterocyclyl.
 21. The compound of claim 1, wherein R₈ is hydrogen.
 22. The compound of claim 1, wherein R₈ is deuterium.
 23. The compound of claim 1, wherein the compound of Formula (I) or the compound of Formula (II) is selected from:

or a pharmaceutically acceptable salt of any of the foregoing.
 24. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt of any of the foregoing, and at least one pharmaceutically acceptable carrier.
 25. A method of treating, ameliorating, or preventing a disease, disorder, or condition associated with TNF-α, INF-γ, IL-2, IL-17, IL-23, or a combination thereof, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt of any of the foregoing, to a subject in need thereof.
 26. The method of claim 25, wherein the disease, disorder, or condition is selected from the group consisting of arthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease, an inflammatory bowel disease, psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis, and combinations thereof.
 27. A method of treating, ameliorating, or preventing a disease, disorder, or condition associated with PDE4, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
 28. The method of claim 27, wherein the disease, disorder, or condition is selected from the group consisting of arthritis, ankylosing spondylitis, osteoarthritis, rheumatoid arthritis, Behcet's disease, an inflammatory bowel disease, psoriasis, psoriatic arthritis, atopic dermatitis, contact dermatitis, and combinations thereof.
 29. A method of decreasing expression of a protein selected from TNF-α, INF-γ, IL-2, IL-17, IL-23, or a combination thereof, comprising contacting a cell with a compound of claim 1, or a pharmaceutically acceptable salt thereof.
 30. The method of claim 29, wherein the protein is TNF-α.
 31. A method of inhibiting PDE4 activity, comprising contacting a cell with a compound of claim 1, or a pharmaceutically acceptable salt thereof.
 32. A method of treating psoriasis, comprising topically administering a therapeutically effective amount of a pharmaceutical composition of claim 24, to a subject in need thereof. 